Dimer Dissociation of a Photoreceptor Protein from QM/MM and MD Simulations

Transcription

1 Dimer Dissociation of a Photoreceptor Protein from QM/MM and MD Simulations IMA University of Minnesota Minneapolis, MN, July 20, 2015 Haisheng Ren Advisor: Prof. Jiali Gao Department of Chemistry, University of Minnesota

2 Outline Introduction UV-B irradiation and photoreceptor protein UVR8 Structural character of UVR8 Multistate density function theory Its application in QM/MM and MD simulations Dimer dissociation of UVR8 Summary

3 Introduction 1. Ultraviolet-B (UV-B) irradiation Wavelengths ( nm) Inducing diverse morphological Deleterious effects on biological molecules and cells and living organisms, including plants Regulating plant growth and development 2. UV-B photoreceptor Arabidopsis thaliana UV Resistance Locus8 (UVR8) protein Dissociation into monomers in response to UV-B irradiation Initiating a sequence of signaling and gene activation events Strid, Å.; Chow, W. S.; Anderson, J. M. UV-B Damage and Protection at the Molecular Level in Plants. Photosynth. Res. 1994, 39,

4 Introduction Structural Features of UVR8 crystal. Interface GLU Asp PDB ID: 4DNW and 4D9S by X-ray crystallography The interface of UVR8 dimer area: Seven pairs tryptophan (red): W233, W285, W337, W250, W94, W302 Six pairs arginines (green): R146 +, R200 +, R234 +, R286 +, R338 +, R354 + Four pairs aspartic acids(pink): D107 -, D96 -, D44 -, D129 - Four pairs glutamic (purple): E53 -, E43 -, E158 -, E182 - Arg Wu D,.etc., Nature 2012, 84: Christie JM, etc.,,. Science 2012, 335:

5 Energy Transfer Introduction Dongping Zhong, J Phys Chem Lett 5 (2014) 69. Trps triads W233, W285 and W337 No other organic dye or cofactor in UVR8 Coworker Prof. Dongping Zhong of Ohio State University found three distinct energy transfer time scales, and W233 is the final excited species Antenna 13 pairs UV-absorbing tryptophan residues : Seven at interface: W94, W198, W233, W250, W285, W302, W337 Six in the middle of beta-strands : W39, W92, W144, W196, W300 and W352

6 Introduction Electron Transfer and Proton Transfer W233(+*) D129(-) PT Trp233* R234 R W233* W285 ET R286 +

7 Possible Mechanisms Wu, Strid, Eriksson, JPCB2014, 118:951. Marcus, PNAS 2014 Xin, Li, Morokuma, etc., JCTC 2014 Introduction To characterize the ET, PT, or PCET processes, and eventually the full energy transfer mechanism of photoactivation, it is important to define the individual local (excited or charge transfer) electronic states, also called diabetic states.

8 Introduction UV-B irradiation and photoreceptor protein UVR8 Structural character of UVR8 Multistate density function theory and its application in QM/MM and MD simulations Dimer dissociation of UVR8 Summary

9 Block-Localized Density functional theory (BLDFT) Multistate is linear combination of each charge localized state and MSDFT is based on the BLDFT to calculate the Hamiltonian of each charge localized state. The fundamental assumption in the BLDFT method is that the total elections and basis functions of the system can be divided into subgroups called blocks or fragments corresponding to the desired charge and spin character Chlorofluoromethyl system [F] - [CH 3 ] + [Cl] - [F] - [CH 3 ] + [Cl] - block-localized MOs Unlike conventional molecular orbital theory or density functional theory, the molecular orbitals of BLDFT are constructed using basis functions with each individual block, or molecular fragment. u N u ˆ - - 1(F ) 2(CH3 ) 3(CI A[ )] Cembran, Song, Mo & Gao, JCTC 2009, 5, 2702.

10 Block-Localized Density functional theory (BLDFT) Features of BLDFT [F] - [F] - [CH 3 ] + [Cl] - block-localized MOs 1. Orbitals in the same block are orthogonal MO. 2. Orbitals in different blocks are nonorthogal VB. [CH 3 ] + [Cl] - The one-particle density matrix : D C T 1 T [( C ) SC ] ( C ) 3. By construction, BLDFT is a rigorously constrained DFT ( A) ( r) dr n u A u A u A u ( r) dr n 0 Cembran, Song, Mo & Gao, JCTC 2009, 5, 2702.

11 Block-Localized Density functional theory (BLDFT) Delocalized charge density Block-localized dimer orbitals Hydrogen-bonding systems in water trimer

12 Multistate density function theory (MSDFT) SN2 reaction Localized Resonance delocalized [F] - [CH [F] - [CH 3 ] + [Cl] - 3 Cl] [FCH 3 ][Cl] - Reactant Transition Product [F - CH 3 Cl] + + H H H H H H H H H H u N u Aˆ[ 1 m ] MSDFT a u u u Effective VB configurations Diabatic states Constrained electronic states Fragment orbitals Resonance delocalized adiabatic ground and excited states MSDFT Hamiltonian can describe the whole reaction from the reactant to the product states, through the transition state Mo & Gao, JPC, 2000, 104, 3012; JCC, 21, Cembran, Song, Mo & Gao, JCTC 2009, 5, Mo, Bao, Gao, Phys Chem Chem Phys 2011, 13, 6760.

13 MSDFT What is MSDFT? Li-Polyaromatic Hydrocarbon Interactions between covalent state and ionic state Covalent state Ionic state

14 MSDFT

15 MSDFT The potential energy surface of a charge separation the distance changes for Li atom and benzene reaction as Li + + C6H6 - Li + C6H6 Ionic state Covalent state

16 MSDFT MSDFT for covalent and ionic mixing KS cov Aˆ{ b ( C H ) ( Li)} 6 6 li KS ion Aˆ{ (C b 6 H 6 ) (Li li )} MSDFT KS cov a c a i KS ion Valence Bond

17 (2.15Å) Adiabatic reaction barrier of 4.5 kcal/mol and excited-ground state energy gap of 15 kcal/mol, indicative of significant coupling.

18 Application in QM/MM MM Part: Classically molecular mechanics ab ab S1 S ) 1 Aˆ{ a b N ( 0 S 1 } N 1 N 1 fragments ( CT ) 1 Aˆ{ a b } N fragments QM Part: MSDFT V ab ab( CT ) H ab( S1) Sab g

19 Application in MD simulation Using charge densities obtained by QM/MM calculation from MSDFT, We can construct the force field for MD simulation

20 Introduction UV-B irradiation and photoreceptor protein UVR8 Structural character of UVR8 Multistate density function theory and its application in QM/MM and MD simulations Dimer dissociation of UVR8 Summary

21 UVR8 MD Simulations/TDDFT/MSDFT The system was embedded in TIP3 water orthorhombic box. Counter ions were added to neutralize charge. All the simulations (wild type, neutralization of R234, R286 and R338) were set up using CHARMM c38a2 and performed with NAMD 2.9 Topologies and parameters were used for all of the calculations according to the CHARMM27 force field with CMAP correction. All the MD simulation are performed for 100 ns atoms

22 MD Simulations UVR8 Key salt bridge (PDB code: 4D9S) R146CZ&E182CD R286CZ&D107CG R338CZ&D44CG R354CZ&E43CD Angst rom 4.07(8) 4.07(8) (7)

23 UVR8 MD Simulations

24 MD Simulation UVR8 Interface

25 MD Simulations UVR8 Wild-type:Blue Neutralization of R234: Yellow Neutralization of R286: Green Neutralization of R338: Red Do RMSD by selecting PROA and aligning PROB

26 UVR8 QM/MM calculation k 4 V h 1 4k G ET rp BT 4 Using BLDFT, we can obtain the diabatic state energy G(R)r, G(P)r, G(P)p and G(R)p. Then the reorganization energy and driving force using linear response: 1 [ G(P) r G(P) p 2 1 [( G(P) G(R)) r 2 ( G(R) G(R) ( G(R) G(P)) p p r ] ] 1 2 exp k B T G o 1 [ G(P) r G(R) 2 1 [( G(P) G(R)) 2 p r ( G(P) G(R) ( G(R) G(P)) p p r ] ] Using MSDFT, we can directly calculate Vrp.

27 UVR8 V DA (mev) G 0 (kcal/mol) λ (kcal/mol) G + (kcal/mol) k et (s -1 ) W233*W285 W233 + W285 - W285 - R286 + W285R286 W285 - R338 + W285R338 Expt: W233*W285 W233 + W G ( G 4 0 ) 2 R286 W285 Averaging calculations of 100 snapshot structures R338 W233 W337 Dongping Zhong, J Phys Chem Lett 5 (2014) 69.

28 Summary MSDFT with Block-localized DFT: VB ( X) auu ( X) aww( X) for studying charge transfer reactions. The photochemical reaction of dimer dissociation mechanism Neutralization of R286 or R338 Direct evidence that capacity of interface increased. Obtained dynamic rate constant of electron transfer

29 Acknowledgments Advisor: Prof. Jiali Gao Dr. Alessandro Cembran Coworker: Prof. Dongping Zhong (OSU) National Institutes of Health National Science Foundation Minnesota Supercomputing Institute Thank you for your attention!!!