Absolute and Relative Binding Free Energy Calculations of Nucleotides to Multiple Protein Classes.

IF 5.7 1区 化学 Q2 CHEMISTRY, PHYSICAL Journal of Chemical Theory and Computation Pub Date : 2024-12-19 DOI:10.1021/acs.jctc.4c01440
Apoorva Purohit, Xiaolin Cheng
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Abstract

Polyphosphate nucleotides, such as ATP, ADP, GTP, and GDP, play a crucial role in modulating protein functions through binding and/or catalytically activating proteins (enzymes). However, accurately calculating the binding free energies for these charged and flexible ligands poses challenges due to slow conformational relaxation and the limitations of force fields. In this study, we examine the accuracy and reliability of alchemical free energy simulations with fixed-charge force fields for the binding of four nucleotides to nine proteins of various classes, including kinases, ATPases, and GTPases. Our results indicate that the alchemical simulations effectively reproduce experimental binding free energies for all proteins that do not undergo significant conformational changes between their triphosphate nucleotide-bound and diphosphate nucleotide-bound states, with 87.5% (7 out of 8) of the absolute binding free energy results for 4 proteins within ±2 kcal/mol of experimental values and 88.9% (8 out of 9) of the relative binding free energy results for 9 proteins within ±3 kcal/mol of experimental values. However, our calculations show significant inaccuracies when divalent ions are included, suggesting that nonpolarizable force fields may not accurately capture interactions involving these ions. Additionally, the presence of highly charged and flexible ligands necessitates extensive conformational sampling to account for the long relaxation times associated with long-range electrostatic interactions. The simulation strategy presented here, along with its demonstrated accuracy across multiple protein classes, will be valuable for predicting the binding of nucleotides or their analogs to protein targets.

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来源期刊
Journal of Chemical Theory and Computation
Journal of Chemical Theory and Computation 化学-物理:原子、分子和化学物理
CiteScore
9.90
自引率
16.40%
发文量
568
审稿时长
1 months
期刊介绍: The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.
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