| Title: | Binding Thermodynamics and Interaction Patterns of Inhibitor-Major Urinary Protein-I Binding from Extensive Free-Energy Calculations: Benchmarking AMBER Force Fields |
| Address: | "State Key Laboratory of Precision Spectroscopy, School of Physics and Electronic Science, East China Normal University, Shanghai 200062, China. Institute of Applied Physics and Materials Engineering, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China" |
| ISSN/ISBN: | 1549-960X (Electronic) 1549-9596 (Linking) |
| Abstract: | "Mouse major urinary protein (MUP) plays a key role in the pheromone communication system. The one-end-closed beta-barrel of MUP-I forms a small, deep, and hydrophobic central cavity, which could accommodate structurally diverse ligands. Previous computational studies employed old protein force fields and short simulation times to determine the binding thermodynamics or investigated only a small number of structurally similar ligands, which resulted in sampled regions far from the experimental structure, nonconverged sampling outcomes, and limited understanding of the possible interaction patterns that the cavity could produce. In this work, extensive end-point and alchemical free-energy calculations with advanced protein force fields were performed to determine the binding thermodynamics of a series of MUP-inhibitor systems and investigate the inter- and intramolecular interaction patterns. Three series of inhibitors with a total of 14 ligands were simulated. We independently simulated the MUP-inhibitor complexes under two advanced AMBER force fields. Our benchmark test showed that the advanced AMBER force fields including AMBER19SB and AMBER14SB provided better descriptions of the system, and the backbone root-mean-square deviation (RMSD) was significantly lowered compared with previous computational studies with old protein force fields. Surprisingly, although the latest AMBER force field AMBER19SB provided better descriptions of various observables, it neither improved the binding thermodynamics nor lowered the backbone RMSD compared with the previously proposed and widely used AMBER14SB. The older but widely used AMBER14SB actually achieved better performance in the prediction of binding affinities from the alchemical and end-point free-energy calculations. We further analyzed the protein-ligand interaction networks to identify important residues stabilizing the bound structure. Six residues including PHE38, LEU40, PHE90, ALA103, LEU105, and TYR120 were found to contribute the most significant part of protein-ligand interactions, and 10 residues were found to provide favorable interactions stabilizing the bound state. The two AMBER force fields gave extremely similar interaction networks, and the secondary structures also showed similar behavior. Thus, the intra- and intermolecular interaction networks described with the two AMBER force fields are similar. Therefore, AMBER14SB could still be the default option in free-energy calculations to achieve highly accurate binding thermodynamics and interaction patterns" |
| Keywords: | Animals *Benchmarking Ligands Mice *Molecular Dynamics Simulation Protein Binding Thermodynamics; |
| Notes: | "MedlineHuai, Zhe Shen, Zhaoxi Sun, Zhaoxi eng Research Support, Non-U.S. Gov't 2020/12/15 J Chem Inf Model. 2021 Jan 25; 61(1):284-297. doi: 10.1021/acs.jcim.0c01217. Epub 2020 Dec 13" |
