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Enhanced Sampling Simulations of Ligand Unbinding Kinetics Controlled by Protein Conformational Changes
AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.
AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.ORCID iD: 0000-0003-1988-7898
AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden.ORCID iD: 0000-0002-3138-820X
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
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2019 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 59, no 9, p. 3910-3918Article in journal (Refereed) Published
Abstract [en]

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-[F-18]fluorodibenzo[b,d]thiophene 5,5-dioxide ([F-18]ASEM) from a chimera structure of the alpha 7-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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2019. Vol. 59, no 9, p. 3910-3918
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Biophysics
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URN: urn:nbn:se:uu:diva-395921DOI: 10.1021/acs.jcim.9b00523ISI: 000487769800034PubMedID: 31454236OAI: oai:DiVA.org:uu-395921DiVA, id: diva2:1366673
Funder
Swedish Foundation for Strategic Research Available from: 2019-10-30 Created: 2019-10-30 Last updated: 2019-10-30Bibliographically approved

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Långström, Bengt

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