Structure and Dynamics of a Dizinc Metalloprotein: Effect of Charge Transfer and Polarization

Li, Yong L.; Ye, Mei; Zhang, Dawei; Xie, Dai Qian; Zhang, John Z. H.

doi:10.1021/jp203505v

Cited by 26 publications

(29 citation statements)

References 55 publications

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“…Although in the PPC scheme, the atomic charge of each residue depends on the conformation of the residue and the chemical environment accommodating it. Therefore, it is more accurate than AMBER charge in delineating the Coulomb interaction within the protein and that in protein/ligand complex . Solvation effect can also be included to polarize the electron distribution in protein.…”

Section: Methodsmentioning

confidence: 99%

The F130L mutation in streptavidin reduces its binding affinity to biotin through electronic polarization effect

et al. 2013

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Recently, Baugh et al. discovered that a distal point mutation (F130L) in streptavidin causes no distinct variation to the structure of the binding pocket but a 1000-fold reduction in biotin binding affinity. In this work, we carry out molecular dynamics simulations and apply an end-state free energy method to calculate the binding free energies of biotin to wild type streptavidin and its F130L mutant. The absolute binding affinities based on AMBER charge are repulsive, and the mutation induced binding loss is underestimated. When using the polarized protein-specific charge, the absolute binding affinities are significantly enhanced. In particular, both the absolute and relative binding affinities are in line with the experimental measurements. Further investigation indicates that polarization effect is indispensable in both the generation of structural ensembles and the calculation of interaction energies. This work verifies Baugh's conjecture that electrostatic polarization effect plays an essential role in modulating the binding affinity of biotin to the streptavidin through F130L mutation.

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Section: Methodsmentioning

confidence: 99%

The F130L mutation in streptavidin reduces its binding affinity to biotin through electronic polarization effect

et al. 2013

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“…Recent research has shown that the performance of MD simulation (Ji et al, 2008;Li, Mei, Zhang, Xie, & Zhang, 2011;Mei et al, 2012;Tong et al, 2010) or proteinligand docking (Cho, Guallar, Berne, & Friesner, 2005;Khandelwal et al, 2005) could be improved using force field parameters (such as atom charges) generated from QM. For example, Mei et al (Ji et al, 2008;Mei et al, 2012;Tong et al, 2010;Zeng, Jia, Zhang, & Mei, 2013) found that the binding free energy calculated using polarizable protein charge obtained from molecular fractionation with conjugate caps (MFCC) protocol is in good agreement with the experimental value, whereas the simulation implemented with conventional non-polarizable force field results in the deviation of simulation results.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamics calculation of protein–ligand interactions by QM/MM polarizable charge parameters

Wang

Shao

Cossins

et al. 2015

Journal of Biomolecular Structure and Dynamics

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The calculation of protein-ligand binding free energy (ΔG) is of great importance for virtual screening and drug design. Molecular dynamics (MD) simulation has been an attractive tool to investigate this scientific problem. However, the reliability of such approach is affected by many factors including electrostatic interaction calculation. Here, we present a practical protocol using quantum mechanics/molecular mechanics (QM/MM) calculations to generate polarizable QM protein charge (QMPC). The calculated QMPC of some atoms in binding pockets was obviously different from that calculated by AMBER ff03, which might significantly affect the calculated ΔG. To evaluate the effect, the MD simulations and MM/GBSA calculation with QMPC for 10 protein-ligand complexes, and the simulation results were then compared to those with the AMBER ff03 force field and experimental results. The correlation coefficient between the calculated ΔΔG using MM/GBSA under QMPC and the experimental data is .92, while that with AMBER ff03 force field is .47 for the complexes formed by streptavidin or its mutants and biotin. Moreover, the calculated ΔΔG with QMPC for the complexes formed by ERβ and five ligands is positively related to experimental result with correlation coefficient of .61, while that with AMBER ff03 charge is negatively related to experimental data with correlation coefficient of .42. The detailed analysis shows that the electrostatic polarization introduced by QMPC affects the electrostatic contribution to the binding affinity and thus, leads to better correlation with experimental data. Therefore, this approach should be useful to virtual screening and drug design.

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“…It is a consensus among the molecular modeling community that including polarization effect into molecular dynamics simulation is both necessary and challenging. There are evidences 26,27 that inclusion of polarization effect could produce experimental phenomenon that classical force field fails to reproduce. Many research groups have studied polarization effect and proposed a number of models [28][29][30][31][32] and techniques to incorporate polarization effect into molecular dynamics.…”

Section: Electrostatic Polarization In Simulationmentioning

confidence: 99%

“…It may be sufficient in this specific case, since the structural variation is not very significant even though tens of hydrogen-bonds were broken and reformed during simulation. Another case study with PPC-update was conducted by Li et.al.. 26 They applied PPC-update to the Zinc binding site of DFsc, a de novo designed dizinc metalloprotein, while keeping charges of other parts of the protein static. Very accurate zinc binding pocket structure was given by PPC-update, way better than structures AMBER parameters gave.…”

Section: Introductionmentioning

confidence: 99%

All-atom molecular dynamics simulation with levels of polarization

Sun¹

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Molecular dynamics (MD) simulation has become an indispensable tool in computational chemistry. It is believed that, to produce reliable results, polarization effect must be included in MD simulation. In this thesis, several studies with MD simulation is conducted with different levels of polarization. First, conventional molecular dynamics simulation without polarization is performed to study interactions between graphene and biomolecules. Interesting results are presented, but more fascinating phenomenon and properties cannot be explored with methods at this level. Then protein molecular dynamics simulations are performed with models representing two levels of polarization, namely fluctuating backbone charge and polarized protein-specific charge updating. The results showed that the newly developed polarized protein-specific charge updating scheme, named ERPPC was promising in several perspectives. It incorporates polarization into MD simulation by varying atomic charges periodically. Simulations show that ERPPC reproduced loop dynamics of enzyme YopH. At the same time, it only consumes about 2.5 times computing time of classical molecular dynamics simulation. Further development

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Structure and Dynamics of a Dizinc Metalloprotein: Effect of Charge Transfer and Polarization

Cited by 26 publications

References 55 publications

The F130L mutation in streptavidin reduces its binding affinity to biotin through electronic polarization effect

The F130L mutation in streptavidin reduces its binding affinity to biotin through electronic polarization effect

Thermodynamics calculation of protein–ligand interactions by QM/MM polarizable charge parameters

All-atom molecular dynamics simulation with levels of polarization

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