Presentation Microcalorimetry for Life Science Research
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1 Presentation Microcalorimetry for Life Science Research
2 MicroCalorimetry The Universal Detector Heat is either generated or absorbed in every chemical process Capable of thermal measurements over a wide variety of solution conditions and temperatures Measures reactions with time scales ranging from a few seconds to several hours ITC Determines affinities from 10 2 to M -1
3 Differential Scanning and Isothermal Titration Calorimetry ITC DSC
4 Measuring Temperature Changes in Calorimetry
5 ITC Temperature Range: 2 o -80 o C Cell Volume: 1.3 or 0.2 ml
6 Representative ITC Data Time (min) al/sec kcal/mole of injectant Data: RNAHHH_NDH Model: 1Sites Chi^2 = N 1.02 ± K 5.57E4 ±1.01E3 H E4 ± Molar Ratio
7 ITC Theoretical Basis G = -RT ln K B G = H T S
8 Primary Causes of Enthalpy and Entropy Enthalpy (- H) Hydrogen bonds Ionic interactions Entropy (+ S) Hydrophobic interactions Conformational freedom
9 ITC: A method for characterizing binding of molecules In a single experiment, ITC can measure binding affinity (K a ), heat of binding and Entropy ( H, S) number of binding sites (n) Multiple binding sites determinable in the same experiment.
10 Typical ITC Applications Molecular Interactions: Proteins, receptors, drugs, nucleic acids, lipids, metals, surfaces, etc. Native Molecules, in solution Quality and process control Enzyme Kinetics Cell metabolism, inhibitors Protein Stability
11 Protein-ligand interactions Tobromycin binding to aminoglycoside nucleotidyltransferase(2 ) Without MgAMPCPP With MgAMPCPP K D = 0.64 µm H = kcal/mole S = -34 cal/mole/ o K K D = 0.21 µm H = kcal/mole S = cal/mole/ o K Wright and Serpersu, Biochemistry 44, (2005)
12 Protein-Protein interactions C-terminal domain of nuclear RNA auxiliary factor (U2AF 65 -UHM) binding to spliceosomal component mutant SF3b155-W7 (shown) or wild-type SF3b155 SF3b155- W7 Wild-type SF3b155 K D (µμ) G (kcal/mol) H (kcal/mol) S (cal/mole/ o K) Thickman et al, J. Mol. Biol. 356, (2006)
13 ITC Applications DNA triplex formation A 120 mm solution of 15-mer single stranded DNA was titrated into a 5mM solution of 23-mer double stranded DNA at 25 o C in 10 mm Sodium Acetate, ph 4.8 K D = 1.1x10-8 DG = kcal/mole DH = kcal/mole DS = e.u Kamiya et al., JACS 118,
14 Thermodynamic Signatures for Drug Binding 10 Scheme A Scheme B Scheme C kcal/mole G H T S MicroCal Application Note: ITC and Drug Design
15 The Evolution of HIV-1 Protease Inhibitors cal/mol G H -T S 12 YEARS Unfavorable Favorable Indinavir Nelfinavir Saquinavir Ritonavir Amprenavir Lopinavir Atazanavir KNI-577 KNI-272 KNI-764 TMC-126 TMC-114 Velazquez-Campoy et al (2003) Current Drug Targets Infectious Disorders, Ohtaka et al (2004) Int. J. Biochem. Cell Biol
16 Optimizing Diaminopyrimidine Renin Inhibitors Aided by ITC Data Sarver, et al, Anal. Biochem. (2007) 360, 30-40
17 The Starting Point A Weak Binder Compound 1 IC 50 = 6.6 µm K d = 3.6 µm? H = kcal/m T? S = kcal/m The IC 50 and K d are not very exciting, but the? H is highly favorable. Why is that? Can this information help us design a better molecule?
18 The Binding Orientation for Cmpd 1 to Renin was Determined by X-ray Crystallography Compound 1 The favorable? H is consistent with the strong network of H-bonds. The low IC 50 and K d are consistent with unoccupied S2 and S3 pockets. So what do we do now?
19 Dramatic Improvement in Enzyme Activity, Binding Affinity and Enthalpy Compound 1 Compound 2 IC 50 = 6,560 nm K d = 3,571 nm? H = kcal/m T? S = kcal/m IC 50 = 691 nm K d = 535 nm? H = kcal/m T? S = kcal/m
20 What Was the Result? Compound 2 Compound 3 IC 50 = 691 nm K d = 535 nm? H = kcal/m T? S = kcal/m IC 50 = 58 nm K d = 79 nm? H = kcal/m T? S = kcal/m Another 10-fold improvement!
21 ITC Applications Antibody Quality Control ITC Studies of two lots of anti-quinidine antibodies Antibody Lot Activity K a (x 10 8 M -1 ) DH (Kcal/mol) Good 90% Bad 12% MicroCal Application Note (1997)
22 ITC Applications Antibody Process Development and Control ITC Studies of immobilized anti-quinidine antibodies Antibody Activity K a (x 10 8 M -1 ) DH (Kcal/mol) Good 90% Immobilized 36% MicroCal Application Note (1997)
23 ITC Applications Enzyme Kinetics
24 ITC Applications Enzyme Kinetics Typical concentrations Enzyme pm Substrate µm (2-20 µl per injection; injections) Todd and Gomez, Anal. Biochem. 296, (2001)
25 ITC Products VP-ITC Cell volume 1.4 ml ~4-5 experiments/8 hours itc 200 Cell volume 0.2 ml experiments /8 hours 7x less sample than VP-ITC Auto-iTC 200 ~50 experiments/day 384 samples, unattended operation Filed upgradeable from itc 200 Available Mid 2008
26 DSC Theory N D Keq = D N
27 DSC Theory? G= -RT lnkeq? G=? H T? S
28 Microcalorimetry DSC Applications Domain structure Formulation and drug stability Yield improvement during chromatography Improve yield during cell culture Membrane studies
29 DSC Data Oligomers T M Shelf-Life/ Stability Binding Cp (kcal/mole/ o C) } C p H Stabilizing Forces/ Energetics Temperature ( o C)
30 Typical DSC Data Data: SAMPLE5DSC_cp Model: M2State Chi^2 = Tm ± H1 1.14E5 ±2.44E3 Tm ± H2 1.47E5 ±2.21E3 kcal/mole Temperature ( o C)
31 Liquid Formulation Stability Evaluation of Excipients Excepient T m ( o C) Control 48.1 Sugars Manitol Glucose Polymers / Polyols PEG (300) Ethanol (low) Ethanol (high) Salts NaCl CaCl Surfactants Pluronic F68 Tween Glucose/NaCl 52.2 Excerpted from: Remmele, et. al., Pharmaceutical Res. 15, (1998)
32 Antibody Stability Effect of Glycosylation Native Partially Deglycosylated Deglycosylated Mimura, et al, J. Biol. Chem. 276, ( 2001)
33 DSC PRODUCTS VP-DSC Cell volume 0.5 ml ~4 samples/8 hours Capillary DSC Cell volume 0.16 ml ~50 samples per day Unattended operation Up to 576 samples on board
34 Conclusions Improved sensitivity and data analysis software have enabled the lab scientist to use the techniques of microcalorimetry for many studies. Heat is a universal detector of biological processes. Microcalorimetry is one of the more versatile technologies available for characterization and analysis of biological molecules.
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