Alchemical Grid Dock (AlGDock): Binding Free Energy Calculations between Flexible Ligands and Rigid Receptors

被引:14
|
作者
Minh, David D. L. [1 ]
机构
[1] IIT, Dept Chem, Chicago, IL 60616 USA
基金
美国国家科学基金会;
关键词
protein-ligand; noncovalent binding free energy; implicit ligand theory; thermodynamic length; replica exchange; PERTURBATION CALCULATIONS; EFFICIENT GENERATION; AM1-BCC MODEL; PREDICTION; SET;
D O I
10.1002/jcc.26036
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Alchemical Grid Dock (AlGDock) is open-source software designed to compute the binding potential of mean force-the binding free energy between a flexible ligand and a rigid receptor-for a small organic ligand and a biological macromolecule. Multiple BPMFs can be used to rigorously compute binding affinities between flexible partners. AlGDock uses replica exchange between thermodynamic states at different temperatures and receptor-ligand interaction strengths. Receptor-ligand interaction energies are represented by interpolating precomputed grids. Thermodynamic states are adaptively initialized and adjusted on-the-fly to maintain adequate replica exchange rates. In demonstrative calculations, when the bound ligand is treated as fully solvated, AlGDock estimates BPMFs with a precision within 4 kT in 65% and within 8 kT for 91% of systems. It correctly identifies the native binding pose in 83% of simulations. Performance is sometimes limited by subtle differences in the important configuration space of sampled and targeted thermodynamic states. (c) 2019 Wiley Periodicals, Inc.
引用
收藏
页码:715 / 730
页数:16
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