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. 2019 Sep 23;59(9):3910-3918.
doi: 10.1021/acs.jcim.9b00523. Epub 2019 Sep 10.

Enhanced Sampling Simulations of Ligand Unbinding Kinetics Controlled by Protein Conformational Changes

Yang Zhou  1 , Rongfeng Zou  1 , Guanglin Kuang  1 , Bengt Långström  2 , Christer Halldin  3 , Hans Ågren  1   4 , Yaoquan Tu  1
Affiliations

Enhanced Sampling Simulations of Ligand Unbinding Kinetics Controlled by Protein Conformational Changes

Yang Zhou et al. J Chem Inf Model. .

Abstract

Understanding unbinding kinetics of protein-ligand systems is of great importance for the design of ligands with desired specificity and safety. In recent years, enhanced sampling techniques have emerged as effective tools for studying unbinding kinetics of protein-ligand systems at the atomistic level. However, in many protein-ligand systems, the ligand unbinding processes are strongly coupled to protein conformational changes and the disclosure of the hidden degrees of freedom closely related to the protein conformational changes so that sampling is enhanced over these degrees of freedom remains a great challenge. Here, we show how potential-scaled molecular dynamics (sMD) and infrequent metadynamics (InMetaD) simulation techniques can be combined to successfully reveal the unbinding mechanism of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[18F]fluo-rodibenzo[b,d]thiophene 5,5-dioxide ([18F]ASEM) from a chimera structure of the α7-nicotinic acetylcholine receptor. By using sMD simulations, we disclosed that the "close" to "open" conformational change of loop C plays a key role in the ASEM unbinding process. By carrying out InMetaD simulations with this conformational change taken into account as an additional collective variable, we further captured the key states in the unbinding process and clarified the unbinding mechanism of ASEM from the protein. Our work indicates that combining sMD and InMetaD simulation techniques can be an effective approach for revealing the unbinding mechanism of a protein-ligand system where protein conformational changes control the unbinding process.

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