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Enhanced Sampling S...
Enhanced Sampling Simulations of Ligand Unbinding Kinetics Controlled by Protein Conformational Changes
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- Zhou, Yang, 1986- (författare)
- KTH,Teoretisk kemi och biologi,Albanova VinnExcellence Center for Protein Technology, ProNova,AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden
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- Zou, Rongfeng (författare)
- KTH,Albanova VinnExcellence Center for Protein Technology, ProNova,Teoretisk kemi och biologi,AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden
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- Guanglin, Kuang, 1987- (författare)
- KTH,Albanova VinnExcellence Center for Protein Technology, ProNova,Teoretisk kemi och biologi,AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden
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- Långström, Bengt (författare)
- Uppsala universitet,Organisk kemi
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- Halidin, Christer (författare)
- Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, S-17176 Stockholm, Sweden.;Stockholm Cty Council, S-17176 Stockholm, Sweden.
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- Ågren, Hans (författare)
- KTH,Albanova VinnExcellence Center for Protein Technology, ProNova,Teoretisk kemi och biologi,AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden;Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China
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- Tu, Yaoquan (författare)
- KTH,Albanova VinnExcellence Center for Protein Technology, ProNova,Teoretisk kemi och biologi,AlbaNova Univ Ctr, KTH Royal Inst Technol, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden
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(creator_code:org_t)
- 2019-08-27
- 2019
- Engelska.
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Ingår i: Journal of Chemical Information and Modeling. - : AMER CHEMICAL SOC. - 1549-9596 .- 1549-960X. ; 59:9, s. 3910-3918
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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]thiophen e 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.
Ämnesord
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)
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