Life Science Webinar Series

Size: px
Start display at page:

Download "Life Science Webinar Series"

Transcription

1 Life Science Webinar Series Elegant protein- protein docking in Discovery Studio Francisco Hernandez-Guzman, Ph.D. November 20, 2007 Sr. Solutions Scientist

2 Agenda In silico protein-protein Docking Why? How? Discovery Studio & Pipeline Pilot Protein-protein Docking algorithms ZDOCK, RDOCK Clustering Added Benefits Visualization (GUI) Clustering, Parallelization Case study DEMO Conclusion 2

3 Why Protein-protein docking? Biological molecules in the body work together to elicit a response Need to understand protein-protein interactions Provide a solid hypothesis for protein interactions Experimental methods X-ray crystallography Difficult, slow, high degree of expertise Experimental bias Applications: Site directed mutagenesis, protein design Molecular detection/screening Affinity binding 3

4 How? Discovery Studio and Pipeline Pilot Protocols (Calculations) can be run in Pipeline Pilot or Discovery Studio 2.0 4

5 Accelrys Discovery Studio Discovery Studio WebPort WebPort (web (web access) access) Pipeline Pipeline Pilot Pilot (Pro or Lite ) (Pro or Lite ) ISV ISV Client Client (e.g., (e.g., Spotfire) Spotfire) Materials Materials Studio Studio Client Client Discovery Discovery Studio Studio Client Client Accord Accord Clients Clients Client Integration Layer S c i i T e g i i c P l l a t t f f o r r m Tool Integration Layer Data Access Layer Cmd-Line Isentris Chemistry Biology Materials Accord Accord IDBS Oracle ISIS Reporting Statistics ISV 5 Tools Databases

6 How? (cnt d) Procedure for Protein-protein docking: Protein preparation stage Docking Stage Rigid docking (ZDOCK) Clustering and Analysis Docked complex refinement and re-ranking (RDOCK) 6

7 Protein preparation stage Protein clean function Problem correction Naming Alternate conformation Incomplete residues Bond orders and connectivity Hydrogen Assignment Ionization based on pk (standard or predicted) Removal of irrelevant elements Waters, crystallization artifacts Forcefield based atom typing (RDOCK) Automatic assignment of topology and parameters Use of CHARMm Polar-H 7

8 Docking Stage Rigid docking (ZDOCK) FFT based initial stage rigid-body docking, efficient systematic search in rotational and translational space PSC pairwise shape complementarity scoring function include options for Blocking and Filtering Clustering and Analysis Uses an RMSD matrix to find largest number of neighbors Algorithm based on ClusPro (Comeau et al. 2004) and Lorenzen et al Docked complex refinement and re-ranking (RDOCK) CHARMm-based procedure for refinement and reranking with electrostatic and ACE desolvation energy Li Li, Rong Chen, Zhiping Weng. Proteins 53: (2003) 8

9 ZDOCK - Rigid Body Docking using Fast Fourier Transform R FFT IFT Correlation L FFT Y X Surface Interior Binding Site 9

10 Grid-based Shape Complementarity 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 0 R GSC L GSC N N N N N N x= y= z= x= y= z= GSC(, l m,) n = Re R(,,) x y z L( x+ l, y+ m, z+ n) Im R(,,) x y z L( x+ l, y+ m, z+ n)

11 Grid-based Shape Complementarity 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i 9i R GSC L GSC N N N N N N x= y= z= x= y= z= GSC(, l m,) n = Re R(,,) x y z L( x+ l, y+ m, z+ n) Im R(,,) x y z L( x+ l, y+ m, z+ n)

12 Pairwise Shape Complementarity i 3i 3i 3i 3i 2 3 3i 9i 3i 3i 3i 2 +3i +3i 3 3i 9i 3i i +3i +9i +9i +3i 3 3i 9i 3i i +3i +9i +9i +3i 3 3i 9i 3i 3i 3i 2 +3i +3i 2 3i 3i 3i 3i 3i R PSC N N N x= y= z= L PSC PSC(, l m, n) = Re R( x, y, z) L( x+ l, y+ m, z+ n)

13 Pairwise Shape Complementarity i 3i 3i 3i 3i 2 3 3i 9i 3i 3i 3i 2+6i +3i 2 +3i 3 3i 9i 3i 5+5i +3i 5 +3i 2+6i 2 +9i +9i +3i 3 3i 9i 3i 5+5i +3i 5 2+6i +3i 2 +9i +9i +3i 3 3i 9i 3i 3i 3i +3i 2+6i 2 +3i 2 3i 3i 3i 3i 3i R PSC N N N x= y= z= L PSC PSC(, l m, n) = Re R( x, y, z) L( x+ l, y+ m, z+ n)

14 4 ZDOCK

15 5 RDOCK

16 Added Benefits: Visualization/Tools (GUI) Coarse grain parallelization Workstation Server 6 Server Server Server

17 Example: In silico Protein-protein docking Docking studies of α-lytic Protease with OMTKY3 & Eglin C Serine Protease catalytic triad His57 Asp02 Ser95 + OMTKY3 =? a-lytic protease (gbk) Currently no experimental 3D structures are available of the complexes (Oct 2007) Eglin C 7

18 OMTKY3 Eglin C 8

19 Docking of α-lytic Protease with OMTKY3 & Eglin C Method: ZDOCK 6 o rotational sampling grid (54000 poses sampled) - filtering residues: catalytic His57 (alp) and P Leu (inhibitors) RDOCK CHARMm 3-stage ABNR minimization: top 50 ZDOCK filtered poses Re-rank based on the RDOCK and ACE scoring functions Results: Top-ranked poses form clusters: reveal expected binding mode - P Leu as leading anchor residue in both complexes Small RMSD in binding loop region among top docked poses Side-chain movement in interface, backbone conformation unchanged Intermolecular h-bonds between binding loop active site 9

20 Docking of α-lytic Protease with OMTKY3 & Eglin C ALP-Eglin C # pose ALP-OMTKY3 # pose V43 T44 L45 D46 L47 C6 T7 L8 E9 Y20 20

21 Publication: Biochemistry. 2006; 45(38):

22 Summary: Protein-protein docking example Correct binding mode identified as # predicted pose in both docking calculations Docking study predictions provide a quantitative energetic measure which supports the experimentally determined much stronger binding strength of Eglin C versus OMTKY3 for α-lytic Protease Desolvation interactions represent an important contributor to the overall stability of both complexes Free energy and desolvation energy successfully discriminate binding strength between both systems 22

23 23 DEMO!!!

24 Conclusion In silico protein docking can be used to derive sensible hypothesis about protein-protein interactions Integration to Discovery Studio allows for easier preparation and analysis of the data, as well as deployment of calculations Graphical utilities complement workflow by providing interactive analysis and manipulation tools for uncovering plausible protein-protein complexes 24

25 Acknowledgements Marc Faschnat Tina Yeh Lisa Yan Paul Flook Shikha O Brien Z-Lab (Prof. Zhiping Weng Boston University) 25

26 References: Chen, R., Li, L. & Weng, Z. (2003) ZDOCK: An Initial-stage Protein Docking Algorithm. Proteins. 52():80-7 Li, L., Chen, R. & Weng, Z. (2003) RDOCK: Refinement of Rigid-body Protein Docking Predictions. Proteins. 53: Wiehe K, Pierce B, Mintseris J, Tong W, Anderson R, Chen R, Weng Z (2005) ZDOCK and RDOCK performance in CAPRI rounds 3, 4, and 5. Proteins. 60(2): Qasim MA, et al. (2006) Despite Having a Common P Leu, Eglin C Inhibits α-lytic Proteinase a Million-fold More Strongly than Does Turkey Ovomucoid Third Domain. Biochemistry. 45(38),

A Rational Approach to Receptor-Flexible Docking: Method and Validation

A Rational Approach to Receptor-Flexible Docking: Method and Validation For audio: Dial-in Information: Toll Free +1 (866) 519 8942 Toll +1 (770) 790 2186 Participant Code: 8587995760 ctober 2007 A Rational Approach to Receptor-Flexible Docking: Method and Validation C. M.

More information

Preparing a PDB File

Preparing a PDB File Figure 1: Schematic view of the ligand-binding domain from the vitamin D receptor (PDB file 1IE9). The crystallographic waters are shown as small spheres and the bound ligand is shown as a CPK model. HO

More information

Chemical properties that affect binding of enzyme-inhibiting drugs to enzymes

Chemical properties that affect binding of enzyme-inhibiting drugs to enzymes Introduction Chemical properties that affect binding of enzyme-inhibiting drugs to enzymes The production of new drugs requires time for development and testing, and can result in large prohibitive costs

More information

Chemical properties that affect binding of enzyme-inhibiting drugs to enzymes

Chemical properties that affect binding of enzyme-inhibiting drugs to enzymes Chemical properties that affect binding of enzyme-inhibiting drugs to enzymes Introduction The production of new drugs requires time for development and testing, and can result in large prohibitive costs

More information

MM-GBSA for Calculating Binding Affinity A rank-ordering study for the lead optimization of Fxa and COX-2 inhibitors

MM-GBSA for Calculating Binding Affinity A rank-ordering study for the lead optimization of Fxa and COX-2 inhibitors MM-GBSA for Calculating Binding Affinity A rank-ordering study for the lead optimization of Fxa and COX-2 inhibitors Thomas Steinbrecher Senior Application Scientist Typical Docking Workflow Databases

More information

Practical QSAR and Library Design: Advanced tools for research teams

Practical QSAR and Library Design: Advanced tools for research teams DS QSAR and Library Design Webinar Practical QSAR and Library Design: Advanced tools for research teams Reservationless-Plus Dial-In Number (US): (866) 519-8942 Reservationless-Plus International Dial-In

More information

User Guide for LeDock

User Guide for LeDock User Guide for LeDock Hongtao Zhao, PhD Email: htzhao@lephar.com Website: www.lephar.com Copyright 2017 Hongtao Zhao. All rights reserved. Introduction LeDock is flexible small-molecule docking software,

More information

Protein-protein interactions of Human Glyoxalase II: findings of a reliable docking protocol

Protein-protein interactions of Human Glyoxalase II: findings of a reliable docking protocol Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry. This journal is The Royal Society of Chemistry 2018 SUPPLEMENTARY INFORMATION Protein-protein interactions of Human Glyoxalase

More information

Docking. GBCB 5874: Problem Solving in GBCB

Docking. GBCB 5874: Problem Solving in GBCB Docking Benzamidine Docking to Trypsin Relationship to Drug Design Ligand-based design QSAR Pharmacophore modeling Can be done without 3-D structure of protein Receptor/Structure-based design Molecular

More information

DISCRETE TUTORIAL. Agustí Emperador. Institute for Research in Biomedicine, Barcelona APPLICATION OF DISCRETE TO FLEXIBLE PROTEIN-PROTEIN DOCKING:

DISCRETE TUTORIAL. Agustí Emperador. Institute for Research in Biomedicine, Barcelona APPLICATION OF DISCRETE TO FLEXIBLE PROTEIN-PROTEIN DOCKING: DISCRETE TUTORIAL Agustí Emperador Institute for Research in Biomedicine, Barcelona APPLICATION OF DISCRETE TO FLEXIBLE PROTEIN-PROTEIN DOCKING: STRUCTURAL REFINEMENT OF DOCKING CONFORMATIONS Emperador

More information

Different conformations of the drugs within the virtual library of FDA approved drugs will be generated.

Different conformations of the drugs within the virtual library of FDA approved drugs will be generated. Chapter 3 Molecular Modeling 3.1. Introduction In this study pharmacophore models will be created to screen a virtual library of FDA approved drugs for compounds that may inhibit MA-A and MA-B. The virtual

More information

Kd = koff/kon = [R][L]/[RL]

Kd = koff/kon = [R][L]/[RL] Taller de docking y cribado virtual: Uso de herramientas computacionales en el diseño de fármacos Docking program GLIDE El programa de docking GLIDE Sonsoles Martín-Santamaría Shrödinger is a scientific

More information

proteins REVIEW Sampling and scoring: A marriage made in heaven Sandor Vajda,* David R. Hall, and Dima Kozakov

proteins REVIEW Sampling and scoring: A marriage made in heaven Sandor Vajda,* David R. Hall, and Dima Kozakov proteins STRUCTURE O FUNCTION O BIOINFORMATICS REVIEW Sampling and scoring: A marriage made in heaven Sandor Vajda,* David R. Hall, and Dima Kozakov Department of Biomedical Engineering, Boston University,

More information

Viewing and Analyzing Proteins, Ligands and their Complexes 2

Viewing and Analyzing Proteins, Ligands and their Complexes 2 2 Viewing and Analyzing Proteins, Ligands and their Complexes 2 Overview Viewing the accessible surface Analyzing the properties of proteins containing thousands of atoms is best accomplished by representing

More information

Retrieving hits through in silico screening and expert assessment M. N. Drwal a,b and R. Griffith a

Retrieving hits through in silico screening and expert assessment M. N. Drwal a,b and R. Griffith a Retrieving hits through in silico screening and expert assessment M.. Drwal a,b and R. Griffith a a: School of Medical Sciences/Pharmacology, USW, Sydney, Australia b: Charité Berlin, Germany Abstract:

More information

Structural energetics of serine protease inhibition*

Structural energetics of serine protease inhibition* Pure Appl. Chem., Vol. 71, No. 7, pp. 1207 1213, 1999. Printed in Great Britain. 1999 IUPAC Structural energetics of serine protease inhibition* Kenneth P. Murphy, Brian M. Baker, Stephen P. Edgcomb and

More information

Enzyme function: the transition state. Enzymes & Kinetics V: Mechanisms. Catalytic Reactions. Margaret A. Daugherty A B. Lecture 16: Fall 2003

Enzyme function: the transition state. Enzymes & Kinetics V: Mechanisms. Catalytic Reactions. Margaret A. Daugherty A B. Lecture 16: Fall 2003 Lecture 16: Enzymes & Kinetics V: Mechanisms Margaret A. Daugherty Fall 2003 Enzyme function: the transition state Catalytic Reactions A B Catalysts (e.g. enzymes) act by lowering the transition state

More information

Catalytic Reactions. Intermediate State in Catalysis. Lecture 16: Catalyzed reaction. Uncatalyzed reaction. Enzymes & Kinetics V: Mechanisms

Catalytic Reactions. Intermediate State in Catalysis. Lecture 16: Catalyzed reaction. Uncatalyzed reaction. Enzymes & Kinetics V: Mechanisms Enzyme function: the transition state Catalytic Reactions Lecture 16: Enzymes & Kinetics V: Mechanisms Margaret A. Daugherty Fall 2003 A B Catalysts (e.g. enzymes) act by lowering the transition state

More information

Introduction to" Protein Structure

Introduction to Protein Structure Introduction to" Protein Structure Function, evolution & experimental methods Thomas Blicher, Center for Biological Sequence Analysis Learning Objectives Outline the basic levels of protein structure.

More information

Lecture 15: Enzymes & Kinetics. Mechanisms ROLE OF THE TRANSITION STATE. H-O-H + Cl - H-O δ- H Cl δ- HO - + H-Cl. Margaret A. Daugherty.

Lecture 15: Enzymes & Kinetics. Mechanisms ROLE OF THE TRANSITION STATE. H-O-H + Cl - H-O δ- H Cl δ- HO - + H-Cl. Margaret A. Daugherty. Lecture 15: Enzymes & Kinetics Mechanisms Margaret A. Daugherty Fall 2004 ROLE OF THE TRANSITION STATE Consider the reaction: H-O-H + Cl - H-O δ- H Cl δ- HO - + H-Cl Reactants Transition state Products

More information

FlexPepDock In a nutshell

FlexPepDock In a nutshell FlexPepDock In a nutshell All Tutorial files are located in http://bit.ly/mxtakv FlexPepdock refinement Step 1 Step 3 - Refinement Step 4 - Selection of models Measure of fit FlexPepdock Ab-initio Step

More information

Structural Bioinformatics (C3210) Molecular Docking

Structural Bioinformatics (C3210) Molecular Docking Structural Bioinformatics (C3210) Molecular Docking Molecular Recognition, Molecular Docking Molecular recognition is the ability of biomolecules to recognize other biomolecules and selectively interact

More information

The Schrödinger KNIME extensions

The Schrödinger KNIME extensions The Schrödinger KNIME extensions Computational Chemistry and Cheminformatics in a workflow environment Jean-Christophe Mozziconacci Volker Eyrich Topics What are the Schrödinger extensions? Workflow application

More information

Dr. Sander B. Nabuurs. Computational Drug Discovery group Center for Molecular and Biomolecular Informatics Radboud University Medical Centre

Dr. Sander B. Nabuurs. Computational Drug Discovery group Center for Molecular and Biomolecular Informatics Radboud University Medical Centre Dr. Sander B. Nabuurs Computational Drug Discovery group Center for Molecular and Biomolecular Informatics Radboud University Medical Centre The road to new drugs. How to find new hits? High Throughput

More information

Homology modeling. Dinesh Gupta ICGEB, New Delhi 1/27/2010 5:59 PM

Homology modeling. Dinesh Gupta ICGEB, New Delhi 1/27/2010 5:59 PM Homology modeling Dinesh Gupta ICGEB, New Delhi Protein structure prediction Methods: Homology (comparative) modelling Threading Ab-initio Protein Homology modeling Homology modeling is an extrapolation

More information

Progress of Compound Library Design Using In-silico Approach for Collaborative Drug Discovery

Progress of Compound Library Design Using In-silico Approach for Collaborative Drug Discovery 21 th /June/2018@CUGM Progress of Compound Library Design Using In-silico Approach for Collaborative Drug Discovery Kaz Ikeda, Ph.D. Keio University Self Introduction Keio University, Tokyo, Japan (Established

More information

Protein Structures. 11/19/2002 Lecture 24 1

Protein Structures. 11/19/2002 Lecture 24 1 Protein Structures 11/19/2002 Lecture 24 1 All 3 figures are cartoons of an amino acid residue. 11/19/2002 Lecture 24 2 Peptide bonds in chains of residues 11/19/2002 Lecture 24 3 Angles φ and ψ in the

More information

Schrodinger ebootcamp #3, Summer EXPLORING METHODS FOR CONFORMER SEARCHING Jas Bhachoo, Senior Applications Scientist

Schrodinger ebootcamp #3, Summer EXPLORING METHODS FOR CONFORMER SEARCHING Jas Bhachoo, Senior Applications Scientist Schrodinger ebootcamp #3, Summer 2016 EXPLORING METHODS FOR CONFORMER SEARCHING Jas Bhachoo, Senior Applications Scientist Numerous applications Generating conformations MM Agenda http://www.schrodinger.com/macromodel

More information

Goals. Structural Analysis of the EGR Family of Transcription Factors: Templates for Predicting Protein DNA Interactions

Goals. Structural Analysis of the EGR Family of Transcription Factors: Templates for Predicting Protein DNA Interactions Structural Analysis of the EGR Family of Transcription Factors: Templates for Predicting Protein DNA Interactions Jamie Duke 1,2 and Carlos Camacho 3 1 Bioengineering and Bioinformatics Summer Institute,

More information

5.1. Hardwares, Softwares and Web server used in Molecular modeling

5.1. Hardwares, Softwares and Web server used in Molecular modeling 5. EXPERIMENTAL The tools, techniques and procedures/methods used for carrying out research work reported in this thesis have been described as follows: 5.1. Hardwares, Softwares and Web server used in

More information

Structure of the α-helix

Structure of the α-helix Structure of the α-helix Structure of the β Sheet Protein Dynamics Basics of Quenching HDX Hydrogen exchange of amide protons is catalyzed by H 2 O, OH -, and H 3 O +, but it s most dominated by base

More information

Enhancing Specificity in the Janus Kinases: A Study on the Thienopyridine. JAK2 Selective Mechanism Combined Molecular Dynamics Simulation

Enhancing Specificity in the Janus Kinases: A Study on the Thienopyridine. JAK2 Selective Mechanism Combined Molecular Dynamics Simulation Electronic Supplementary Material (ESI) for Molecular BioSystems. This journal is The Royal Society of Chemistry 2015 Supporting Information Enhancing Specificity in the Janus Kinases: A Study on the Thienopyridine

More information

Using Bayesian Statistics to Predict Water Affinity and Behavior in Protein Binding Sites. J. Andrew Surface

Using Bayesian Statistics to Predict Water Affinity and Behavior in Protein Binding Sites. J. Andrew Surface Using Bayesian Statistics to Predict Water Affinity and Behavior in Protein Binding Sites Introduction J. Andrew Surface Hampden-Sydney College / Virginia Commonwealth University In the past several decades

More information

Lecture # 3, 4 Selecting a Catalyst (Non-Kinetic Parameters), Review of Enzyme Kinetics, Selectivity, ph and Temperature Effects

Lecture # 3, 4 Selecting a Catalyst (Non-Kinetic Parameters), Review of Enzyme Kinetics, Selectivity, ph and Temperature Effects 1.492 - Integrated Chemical Engineering (ICE Topics: Biocatalysis MIT Chemical Engineering Department Instructor: Professor Kristala Prather Fall 24 Lecture # 3, 4 Selecting a Catalyst (Non-Kinetic Parameters,

More information

Molecular Mechanics, Dynamics & Docking

Molecular Mechanics, Dynamics & Docking Molecular Mechanics, Dynamics & Docking Lawrence Hunter, Ph.D. Director, Computational Bioscience Program University of Colorado School of Medicine Larry.Hunter@uchsc.edu http://compbio.uchsc.edu/hunter

More information

Portal. User Guide Version 1.0. Contributors

Portal.   User Guide Version 1.0. Contributors Portal www.dockthor.lncc.br User Guide Version 1.0 Contributors Diogo A. Marinho, Isabella A. Guedes, Eduardo Krempser, Camila S. de Magalhães, Hélio J. C. Barbosa and Laurent E. Dardenne www.gmmsb.lncc.br

More information

Softwares for Molecular Docking. Lokesh P. Tripathi NCBS 17 December 2007

Softwares for Molecular Docking. Lokesh P. Tripathi NCBS 17 December 2007 Softwares for Molecular Docking Lokesh P. Tripathi NCBS 17 December 2007 Molecular Docking Attempt to predict structures of an intermolecular complex between two or more molecules Receptor-ligand (or drug)

More information

GC and CELPP: Workflows and Insights

GC and CELPP: Workflows and Insights GC and CELPP: Workflows and Insights Xianjin Xu, Zhiwei Ma, Rui Duan, Xiaoqin Zou Dalton Cardiovascular Research Center, Department of Physics and Astronomy, Department of Biochemistry, & Informatics Institute

More information

Tools for Cryo-EM Map Fitting. Paul Emsley MRC Laboratory of Molecular Biology

Tools for Cryo-EM Map Fitting. Paul Emsley MRC Laboratory of Molecular Biology Tools for Cryo-EM Map Fitting Paul Emsley MRC Laboratory of Molecular Biology April 2017 Cryo-EM model-building typically need to move more atoms that one does for crystallography the maps are lower resolution

More information

Using AutoDock for Virtual Screening

Using AutoDock for Virtual Screening Using AutoDock for Virtual Screening CUHK Croucher ASI Workshop 2011 Stefano Forli, PhD Prof. Arthur J. Olson, Ph.D Molecular Graphics Lab Screening and Virtual Screening The ultimate tool for identifying

More information

Details of Protein Structure

Details of Protein Structure Details of Protein Structure Function, evolution & experimental methods Thomas Blicher, Center for Biological Sequence Analysis Anne Mølgaard, Kemisk Institut, Københavns Universitet Learning Objectives

More information

BSc and MSc Degree Examinations

BSc and MSc Degree Examinations Examination Candidate Number: Desk Number: BSc and MSc Degree Examinations 2018-9 Department : BIOLOGY Title of Exam: Molecular Biology and Biochemistry Part I Time Allowed: 1 hour and 30 minutes Marking

More information

Structural biology and drug design: An overview

Structural biology and drug design: An overview Structural biology and drug design: An overview livier Taboureau Assitant professor Chemoinformatics group-cbs-dtu otab@cbs.dtu.dk Drug discovery Drug and drug design A drug is a key molecule involved

More information

Joana Pereira Lamzin Group EMBL Hamburg, Germany. Small molecules How to identify and build them (with ARP/wARP)

Joana Pereira Lamzin Group EMBL Hamburg, Germany. Small molecules How to identify and build them (with ARP/wARP) Joana Pereira Lamzin Group EMBL Hamburg, Germany Small molecules How to identify and build them (with ARP/wARP) The task at hand To find ligand density and build it! Fitting a ligand We have: electron

More information

Proteins are not rigid structures: Protein dynamics, conformational variability, and thermodynamic stability

Proteins are not rigid structures: Protein dynamics, conformational variability, and thermodynamic stability Proteins are not rigid structures: Protein dynamics, conformational variability, and thermodynamic stability Dr. Andrew Lee UNC School of Pharmacy (Div. Chemical Biology and Medicinal Chemistry) UNC Med

More information

CSD. CSD-Enterprise. Access the CSD and ALL CCDC application software

CSD. CSD-Enterprise. Access the CSD and ALL CCDC application software CSD CSD-Enterprise Access the CSD and ALL CCDC application software CSD-Enterprise brings it all: access to the Cambridge Structural Database (CSD), the world s comprehensive and up-to-date database of

More information

Protein Structure Prediction

Protein Structure Prediction Page 1 Protein Structure Prediction Russ B. Altman BMI 214 CS 274 Protein Folding is different from structure prediction --Folding is concerned with the process of taking the 3D shape, usually based on

More information

Autodock tutorial VINA with UCSF Chimera

Autodock tutorial VINA with UCSF Chimera Autodock tutorial VINA with UCSF Chimera José R. Valverde CNB/CSIC jrvalverde@cnb.csic.es José R. Valverde, 2014 CC-BY-NC-SA Loading the receptor Open UCSF Chimera and then load the protein: File Open

More information

DOCKING TUTORIAL. A. The docking Workflow

DOCKING TUTORIAL. A. The docking Workflow 2 nd Strasbourg Summer School on Chemoinformatics VVF Obernai, France, 20-24 June 2010 E. Kellenberger DOCKING TUTORIAL A. The docking Workflow 1. Ligand preparation It consists in the standardization

More information

Protein structure prediction. CS/CME/BioE/Biophys/BMI 279 Oct. 10 and 12, 2017 Ron Dror

Protein structure prediction. CS/CME/BioE/Biophys/BMI 279 Oct. 10 and 12, 2017 Ron Dror Protein structure prediction CS/CME/BioE/Biophys/BMI 279 Oct. 10 and 12, 2017 Ron Dror 1 Outline Why predict protein structure? Can we use (pure) physics-based methods? Knowledge-based methods Two major

More information

Design of a Novel Globular Protein Fold with Atomic-Level Accuracy

Design of a Novel Globular Protein Fold with Atomic-Level Accuracy Design of a Novel Globular Protein Fold with Atomic-Level Accuracy Brian Kuhlman, Gautam Dantas, Gregory C. Ireton, Gabriele Varani, Barry L. Stoddard, David Baker Presented by Kate Stafford 4 May 05 Protein

More information

Examples of Protein Modeling. Protein Modeling. Primary Structure. Protein Structure Description. Protein Sequence Sources. Importing Sequences to MOE

Examples of Protein Modeling. Protein Modeling. Primary Structure. Protein Structure Description. Protein Sequence Sources. Importing Sequences to MOE Examples of Protein Modeling Protein Modeling Visualization Examination of an experimental structure to gain insight about a research question Dynamics To examine the dynamics of protein structures To

More information

Cheminformatics platform for drug discovery application

Cheminformatics platform for drug discovery application EGI-InSPIRE Cheminformatics platform for drug discovery application Hsi-Kai, Wang Academic Sinica Grid Computing EGI User Forum, 13, April, 2011 1 Introduction to drug discovery Computing requirement of

More information

Free Energy Landscapes of Encounter Complexes in Protein-Protein Association

Free Energy Landscapes of Encounter Complexes in Protein-Protein Association 1166 Biophysical Journal Volume 76 March 1999 1166 1178 Free Energy Landscapes of Encounter Complexes in Protein-Protein Association Carlos J. Camacho, Zhiping Weng, Sandor Vajda, and Charles DeLisi Department

More information

Protein Dynamics. The space-filling structures of myoglobin and hemoglobin show that there are no pathways for O 2 to reach the heme iron.

Protein Dynamics. The space-filling structures of myoglobin and hemoglobin show that there are no pathways for O 2 to reach the heme iron. Protein Dynamics The space-filling structures of myoglobin and hemoglobin show that there are no pathways for O 2 to reach the heme iron. Below is myoglobin hydrated with 350 water molecules. Only a small

More information

Analysis and Prediction of Protein Structure (I)

Analysis and Prediction of Protein Structure (I) Analysis and Prediction of Protein Structure (I) Jianlin Cheng, PhD School of Electrical Engineering and Computer Science University of Central Florida 2006 Free for academic use. Copyright @ Jianlin Cheng

More information

Mechanistic insight into inhibition of two-component system signaling

Mechanistic insight into inhibition of two-component system signaling Supporting Information Mechanistic insight into inhibition of two-component system signaling Samson Francis, a Kaelyn E. Wilke, a Douglas E. Brown a and Erin E. Carlson a,b* a Department of Chemistry,

More information

BUDE. A General Purpose Molecular Docking Program Using OpenCL. Richard B Sessions

BUDE. A General Purpose Molecular Docking Program Using OpenCL. Richard B Sessions BUDE A General Purpose Molecular Docking Program Using OpenCL Richard B Sessions 1 The molecular docking problem receptor ligand Proteins typically O(1000) atoms Ligands typically O(100) atoms predicted

More information

Virtual affinity fingerprints in drug discovery: The Drug Profile Matching method

Virtual affinity fingerprints in drug discovery: The Drug Profile Matching method Ágnes Peragovics Virtual affinity fingerprints in drug discovery: The Drug Profile Matching method PhD Theses Supervisor: András Málnási-Csizmadia DSc. Associate Professor Structural Biochemistry Doctoral

More information

Francisco Melo, Damien Devos, Eric Depiereux and Ernest Feytmans

Francisco Melo, Damien Devos, Eric Depiereux and Ernest Feytmans From: ISMB-97 Proceedings. Copyright 1997, AAAI (www.aaai.org). All rights reserved. ANOLEA: A www Server to Assess Protein Structures Francisco Melo, Damien Devos, Eric Depiereux and Ernest Feytmans Facultés

More information

Structure to Function. Molecular Bioinformatics, X3, 2006

Structure to Function. Molecular Bioinformatics, X3, 2006 Structure to Function Molecular Bioinformatics, X3, 2006 Structural GeNOMICS Structural Genomics project aims at determination of 3D structures of all proteins: - organize known proteins into families

More information

CHAPTER 3. Pharmacophore modelling studies:

CHAPTER 3. Pharmacophore modelling studies: CHAPTER 3 Pharmacophore modelling studies: 3.1 Introduction: According to Langer & Wolber (2004), the key goal of computer-aided molecular design methods in medicinal chemistry is to reduce the time and

More information

The Conformation Search Problem

The Conformation Search Problem Jon Sutter Senior Manager Life Sciences R&D jms@accelrys.com Jiabo Li Senior Scientist Life Sciences R&D jli@accelrys.com CAESAR: Conformer Algorithm based on Energy Screening and Recursive Buildup The

More information

Structural Perspectives on Drug Resistance

Structural Perspectives on Drug Resistance Structural Perspectives on Drug Resistance Irene Weber Departments of Biology and Chemistry Molecular Basis of Disease Program Georgia State University Atlanta, GA, USA What have we learned from 20 years

More information

Advanced Certificate in Principles in Protein Structure. You will be given a start time with your exam instructions

Advanced Certificate in Principles in Protein Structure. You will be given a start time with your exam instructions BIRKBECK COLLEGE (University of London) Advanced Certificate in Principles in Protein Structure MSc Structural Molecular Biology Date: Thursday, 1st September 2011 Time: 3 hours You will be given a start

More information

Protein sidechain conformer prediction: a test of the energy function Robert J Petrella 1, Themis Lazaridis 1 and Martin Karplus 1,2

Protein sidechain conformer prediction: a test of the energy function Robert J Petrella 1, Themis Lazaridis 1 and Martin Karplus 1,2 Research Paper 353 Protein sidechain conformer prediction: a test of the energy function Robert J Petrella 1, Themis Lazaridis 1 and Martin Karplus 1,2 Background: Homology modeling is an important technique

More information

Life Sciences 1a Lecture Slides Set 10 Fall Prof. David R. Liu. Lecture Readings. Required: Lecture Notes McMurray p , O NH

Life Sciences 1a Lecture Slides Set 10 Fall Prof. David R. Liu. Lecture Readings. Required: Lecture Notes McMurray p , O NH Life ciences 1a Lecture lides et 10 Fall 2006-2007 Prof. David R. Liu Lectures 17-18: The molecular basis of drug-protein binding: IV protease inhibitors 1. Drug development and its impact on IV-infected

More information

Homology Modeling (Comparative Structure Modeling) GBCB 5874: Problem Solving in GBCB

Homology Modeling (Comparative Structure Modeling) GBCB 5874: Problem Solving in GBCB Homology Modeling (Comparative Structure Modeling) Aims of Structural Genomics High-throughput 3D structure determination and analysis To determine or predict the 3D structures of all the proteins encoded

More information

Supplementary Figure S1. Urea-mediated buffering mechanism of H. pylori. Gastric urea is funneled to a cytoplasmic urease that is presumably attached

Supplementary Figure S1. Urea-mediated buffering mechanism of H. pylori. Gastric urea is funneled to a cytoplasmic urease that is presumably attached Supplementary Figure S1. Urea-mediated buffering mechanism of H. pylori. Gastric urea is funneled to a cytoplasmic urease that is presumably attached to HpUreI. Urea hydrolysis products 2NH 3 and 1CO 2

More information

Introduction to Structure Preparation and Visualization

Introduction to Structure Preparation and Visualization Introduction to Structure Preparation and Visualization Created with: Release 2018-4 Prerequisites: Release 2018-2 or higher Access to the internet Categories: Molecular Visualization, Structure-Based

More information

Visualization of Macromolecular Structures

Visualization of Macromolecular Structures Visualization of Macromolecular Structures Present by: Qihang Li orig. author: O Donoghue, et al. Structural biology is rapidly accumulating a wealth of detailed information. Over 60,000 high-resolution

More information

Protein Structures: Experiments and Modeling. Patrice Koehl

Protein Structures: Experiments and Modeling. Patrice Koehl Protein Structures: Experiments and Modeling Patrice Koehl Structural Bioinformatics: Proteins Proteins: Sources of Structure Information Proteins: Homology Modeling Proteins: Ab initio prediction Proteins:

More information

Toward an Understanding of GPCR-ligand Interactions. Alexander Heifetz

Toward an Understanding of GPCR-ligand Interactions. Alexander Heifetz Toward an Understanding of GPCR-ligand Interactions Alexander Heifetz UK QSAR and ChemoInformatics Group Conference, Cambridge, UK October 6 th, 2015 Agenda Fragment Molecular Orbitals (FMO) for GPCR exploration

More information

Combination of Scoring Functions Improves Discrimination in Protein Protein Docking

Combination of Scoring Functions Improves Discrimination in Protein Protein Docking PROTEINS: Structure, Function, and Genetics 52:000 000 (2003) AQ: 1 Combination of Scoring Functions Improves Discrimination in Protein Protein Docking John Murphy, David W. Gatchell, Jahnavi C. Prasad,

More information

Towards Physics-based Models for ADME/Tox. Tyler Day

Towards Physics-based Models for ADME/Tox. Tyler Day Towards Physics-based Models for ADME/Tox Tyler Day Overview Motivation Application: P450 Site of Metabolism Application: Membrane Permeability Future Directions and Applications Motivation Advantages

More information

Biologically Relevant Molecular Comparisons. Mark Mackey

Biologically Relevant Molecular Comparisons. Mark Mackey Biologically Relevant Molecular Comparisons Mark Mackey Agenda > Cresset Technology > Cresset Products > FieldStere > FieldScreen > FieldAlign > FieldTemplater > Cresset and Knime About Cresset > Specialist

More information

Cross Discipline Analysis made possible with Data Pipelining. J.R. Tozer SciTegic

Cross Discipline Analysis made possible with Data Pipelining. J.R. Tozer SciTegic Cross Discipline Analysis made possible with Data Pipelining J.R. Tozer SciTegic System Genesis Pipelining tool created to automate data processing in cheminformatics Modular system built with generic

More information

In silico pharmacology for drug discovery

In silico pharmacology for drug discovery In silico pharmacology for drug discovery In silico drug design In silico methods can contribute to drug targets identification through application of bionformatics tools. Currently, the application of

More information

Protein Structure Analysis and Verification. Course S Basics for Biosystems of the Cell exercise work. Maija Nevala, BIO, 67485U 16.1.

Protein Structure Analysis and Verification. Course S Basics for Biosystems of the Cell exercise work. Maija Nevala, BIO, 67485U 16.1. Protein Structure Analysis and Verification Course S-114.2500 Basics for Biosystems of the Cell exercise work Maija Nevala, BIO, 67485U 16.1.2008 1. Preface When faced with an unknown protein, scientists

More information

Protein structure sampling based on molecular dynamics and improvement of docking prediction

Protein structure sampling based on molecular dynamics and improvement of docking prediction 1 1 1, 2 1 NMR X Protein structure sampling based on molecular dynamics and improvement of docking prediction Yusuke Matsuzaki, 1 Yuri Matsuzaki, 1 Masakazu Sekijima 1, 2 and Yutaka Akiyama 1 When a protein

More information

Identifying Interaction Hot Spots with SuperStar

Identifying Interaction Hot Spots with SuperStar Identifying Interaction Hot Spots with SuperStar Version 1.0 November 2017 Table of Contents Identifying Interaction Hot Spots with SuperStar... 2 Case Study... 3 Introduction... 3 Generate SuperStar Maps

More information

Data Quality Issues That Can Impact Drug Discovery

Data Quality Issues That Can Impact Drug Discovery Data Quality Issues That Can Impact Drug Discovery Sean Ekins 1, Joe Olechno 2 Antony J. Williams 3 1 Collaborations in Chemistry, Fuquay Varina, NC. 2 Labcyte Inc, Sunnyvale, CA. 3 Royal Society of Chemistry,

More information

Supplementary Figure 3 a. Structural comparison between the two determined structures for the IL 23:MA12 complex. The overall RMSD between the two

Supplementary Figure 3 a. Structural comparison between the two determined structures for the IL 23:MA12 complex. The overall RMSD between the two Supplementary Figure 1. Biopanningg and clone enrichment of Alphabody binders against human IL 23. Positive clones in i phage ELISA with optical density (OD) 3 times higher than background are shown for

More information

Introduction to Comparative Protein Modeling. Chapter 4 Part I

Introduction to Comparative Protein Modeling. Chapter 4 Part I Introduction to Comparative Protein Modeling Chapter 4 Part I 1 Information on Proteins Each modeling study depends on the quality of the known experimental data. Basis of the model Search in the literature

More information

Lecture 10 (10/4/17) Lecture 10 (10/4/17)

Lecture 10 (10/4/17) Lecture 10 (10/4/17) Lecture 10 (10/4/17) Reading: Ch4; 125, 138-141, 141-142 Problems: Ch4 (text); 7, 9, 11 Ch4 (study guide); 1, 2 NEXT Reading: Ch4; 125, 132-136 (structure determination) Ch4; 12-130 (Collagen) Problems:

More information

Protein Docking by Exploiting Multi-dimensional Energy Funnels

Protein Docking by Exploiting Multi-dimensional Energy Funnels Protein Docking by Exploiting Multi-dimensional Energy Funnels Ioannis Ch. Paschalidis 1 Yang Shen 1 Pirooz Vakili 1 Sandor Vajda 2 1 Center for Information and Systems Engineering and Department of Manufacturing

More information

A. Reaction Mechanisms and Catalysis (1) proximity effect (2) acid-base catalysts (3) electrostatic (4) functional groups (5) structural flexibility

A. Reaction Mechanisms and Catalysis (1) proximity effect (2) acid-base catalysts (3) electrostatic (4) functional groups (5) structural flexibility (P&S Ch 5; Fer Ch 2, 9; Palm Ch 10,11; Zub Ch 9) A. Reaction Mechanisms and Catalysis (1) proximity effect (2) acid-base catalysts (3) electrostatic (4) functional groups (5) structural flexibility B.

More information

MD Simulation in Pose Refinement and Scoring Using AMBER Workflows

MD Simulation in Pose Refinement and Scoring Using AMBER Workflows MD Simulation in Pose Refinement and Scoring Using AMBER Workflows Yuan Hu (On behalf of Merck D3R Team) D3R Grand Challenge 2 Webinar Department of Chemistry, Modeling & Informatics Merck Research Laboratories,

More information

Complex Structure Modeling

Complex Structure Modeling Molecular Modeling and Simulation On June 8, 2015 Complex Structure Modeling Agricultural Bioinformatics Research Unit, Graduate School of Agricultural and Life Sciences, The University of Tokyo Tohru

More information

Today s lecture. Molecular Mechanics and docking. Lecture 22. Introduction to Bioinformatics Docking - ZDOCK. Protein-protein docking

Today s lecture. Molecular Mechanics and docking. Lecture 22. Introduction to Bioinformatics Docking - ZDOCK. Protein-protein docking C N F O N G A V B O N F O M A C S V U Molecular Mechanics and docking Lecture 22 ntroduction to Bioinformatics 2007 oday s lecture 1. Protein interaction and docking a) Zdock method 2. Molecular motion

More information

Fast, Intuitive Structure Determination IV: Space Group Determination and Structure Solution

Fast, Intuitive Structure Determination IV: Space Group Determination and Structure Solution Fast, Intuitive Structure Determination IV: Space Group Determination and Structure Solution November 25, 2013 Welcome I I Dr. Michael Ruf Product Manager Crystallography Bruker AXS Inc. Madison, WI, USA

More information

Structure Investigation of Fam20C, a Golgi Casein Kinase

Structure Investigation of Fam20C, a Golgi Casein Kinase Structure Investigation of Fam20C, a Golgi Casein Kinase Sharon Grubner National Taiwan University, Dr. Jung-Hsin Lin University of California San Diego, Dr. Rommie Amaro Abstract This research project

More information

Using Higher Calculus to Study Biologically Important Molecules Julie C. Mitchell

Using Higher Calculus to Study Biologically Important Molecules Julie C. Mitchell Using Higher Calculus to Study Biologically Important Molecules Julie C. Mitchell Mathematics and Biochemistry University of Wisconsin - Madison 0 There Are Many Kinds Of Proteins The word protein comes

More information

The PhilOEsophy. There are only two fundamental molecular descriptors

The PhilOEsophy. There are only two fundamental molecular descriptors The PhilOEsophy There are only two fundamental molecular descriptors Where can we use shape? Virtual screening More effective than 2D Lead-hopping Shape analogues are not graph analogues Molecular alignment

More information

Virtual Screening: How Are We Doing?

Virtual Screening: How Are We Doing? Virtual Screening: How Are We Doing? Mark E. Snow, James Dunbar, Lakshmi Narasimhan, Jack A. Bikker, Dan Ortwine, Christopher Whitehead, Yiannis Kaznessis, Dave Moreland, Christine Humblet Pfizer Global

More information

Molecular modeling with InsightII

Molecular modeling with InsightII Molecular modeling with InsightII Yuk Sham Computational Biology/Biochemistry Consultant Phone: (612) 624 7427 (Walter Library) Phone: (612) 624 0783 (VWL) Email: shamy@msi.umn.edu How to run InsightII

More information

4 Examples of enzymes

4 Examples of enzymes Catalysis 1 4 Examples of enzymes Adding water to a substrate: Serine proteases. Carbonic anhydrase. Restrictions Endonuclease. Transfer of a Phosphoryl group from ATP to a nucleotide. Nucleoside monophosphate

More information

Receptor Based Drug Design (1)

Receptor Based Drug Design (1) Induced Fit Model For more than 100 years, the behaviour of enzymes had been explained by the "lock-and-key" mechanism developed by pioneering German chemist Emil Fischer. Fischer thought that the chemicals

More information

BBS501 Section 1 9:00 am 10:00 am Monday thru Friday LRC 105 A & B

BBS501 Section 1 9:00 am 10:00 am Monday thru Friday LRC 105 A & B BBS501 Section 1 9:00 am 10:00 am Monday thru Friday LRC 105 A & B Lecturers: Dr. Yie-Hwa Chang Room M130 Phone: #79263 E-mail:changy@slu.edu Dr. Tomasz Heyduk Room M99 Phone: #79238 E-mail: heydukt@slu.edu

More information

Overview & Applications. T. Lezon Hands-on Workshop in Computational Biophysics Pittsburgh Supercomputing Center 04 June, 2015

Overview & Applications. T. Lezon Hands-on Workshop in Computational Biophysics Pittsburgh Supercomputing Center 04 June, 2015 Overview & Applications T. Lezon Hands-on Workshop in Computational Biophysics Pittsburgh Supercomputing Center 4 June, 215 Simulations still take time Bakan et al. Bioinformatics 211. Coarse-grained Elastic

More information