Massively parallel computation of absolute binding free energy with well-equilibrated states

作     者：Hideaki Fujitani Yoshiaki Tanida Azuma Matsuura 

作者机构：Fujitsu Laboratories Ltd. 10-1 Morinosato-Wakamiya Atsugi 243-0197 Japan 

出 版 物：《Physical Review E》 (物理学评论E辑：统计、非线性和软体物理学)

年 卷 期：2009年第79卷第2期

页      面：021914-021914页

核心收录：

学科分类：07[理学] 070203[理学-原子与分子物理] 0702[理学-物理学] 

基　　金：High-Throughput Biomolecule Analysis System Project of NEDO (New Energy and Industrial Technology Development Organization  Japan) 

主　　题：binding energy free energy molecular force constants organic compounds parallel algorithms MOLECULAR-DYNAMICS SIMULATIONS AMBER FORCE-FIELD EFFICIENT GENERATION ATOMIC CHARGES AM1-BCC MODEL NUCLEIC-ACIDS ENSEMBLE RNA POTENTIALS STABILITY 

摘      要：A force field formulator for organic molecules (FF-FOM) was developed to assign bond, angle, and dihedral parameters to arbitrary organic molecules in a unified manner including proteins and nucleic acids. With the unified force field parametrization we performed massively parallel computations of absolute binding free energies for pharmaceutical target proteins and ligands. Compared with the previous calculation with the ff99 force field in the Amber simulation package (Amber99) and the ligand charges produced by the Austin Model 1 bond charge correction (AM1-BCC), the unified parametrization gave better absolute binding energies for the FK506 binding protein (FKBP) and ligand system. Our method is based on extensive work measurement between thermodynamic states to calculate the free energy difference and it is also the same as the traditional free energy perturbation. There are important requirements for accurate calculations. The first is a well-equilibrated bound structure including the conformational change of the protein induced by the binding of the ligand. The second requirement is the convergence of the work distribution with a sufficient number of trajectories and dense spacing of the coupling constant between the ligand and the rest of the system. Finally, the most important requirement is the force field parametrization.