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平衡和非平衡方法计算相对结合自由能的精度和效率比较
李鹏飞,贾相瑜,王美婷,梅晔*
作者单位E-mail
李鹏飞 华东师范大学物理与材料科学学院精密光谱科学与技术国家重点实验室, 上海 200062  
贾相瑜 华东师范大学物理与材料科学学院精密光谱科学与技术国家重点实验室, 上海 200062;华东师范大学-上海纽约大学计算化学联合中心, 上海 200062  
王美婷 华东师范大学物理与材料科学学院精密光谱科学与技术国家重点实验室, 上海 200062  
梅晔* 华东师范大学物理与材料科学学院精密光谱科学与技术国家重点实验室, 上海 200062;华东师范大学-上海纽约大学计算化学联合中心, 上海 200062;俄克拉荷马大学化学和生物化学系, 诺曼 73019 ymei@phy.ecnu.edu.cn 
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DOI:10.1063/1674-0068/30/cjcp1711204
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基金项目:This work is supported by the National Natural Science Foundation of China (No.21773066).
Comparison of Accuracy and Convergence Rate between Equilibrium and Nonequilibrium Alchemical Transformations for Calculation of Relative Binding Free Energy
Peng-fei Li,Xiang-yu Jia,Mei-ting Wang,Ye Mei*
Abstract:
Estimation of protein-ligand binding affinity within chemical accuracy is one of the grand challenges in structure-based rational drug design. With the efforts over three decades, free energy methods based on equilibrium molecular dynamics (MD) simulations have become mature and are nowadays routinely applied in the community of computational chemistry. On the contrary, nonequilibrium MD simulation methods have attracted less attention, despite their underlying rigor in mathematics and potential advantage in efficiency. In this work, the equilibrium and nonequilibrium simulation methods are compared in terms of accuracy and convergence rate in the calculations of relative binding free energies. The proteins studied are T4-lysozyme mutant L99A and COX-2. For each protein, two ligands are studied. The results show that the nonequilibrium simulation method can be competitively as accurate as the equilibrium method, and the former is more efficient than the latter by considering the convergence rate with respect to the cost of wall clock time. In addition, Bennett acceptance ratio, which is a bidirectional post-processing method, converges faster than the unidirectional Jarzynski equality for the nonequilibrium simulations.
Key words:  Free energy  Equilibrium  Nonequilibrium  Convergence rate  Accuracy