دورية أكاديمية
أعرض في EDS

Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo and Molecular Dynamics.

التفاصيل البيبلوغرافية
العنوان: Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo and Molecular Dynamics.
المؤلفون: Sasmal S; Department of Pharmaceutical Sciences, University of California, Irvine, California 92697, United States., Gill SC; Department of Chemistry, University of California, Irvine, California 92697, United States., Lim NM; Department of Pharmaceutical Sciences, University of California, Irvine, California 92697, United States., Mobley DL; Department of Chemistry, University of California, Irvine, California 92697, United States.; Department of Pharmaceutical Sciences, University of California, Irvine, California 92697, United States.
المصدر: Journal of chemical theory and computation [J Chem Theory Comput] 2020 Mar 10; Vol. 16 (3), pp. 1854-1865. Date of Electronic Publication: 2020 Feb 24.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101232704 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-9626 (Electronic) Linking ISSN: 15499618 NLM ISO Abbreviation: J Chem Theory Comput Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society, c2005-
مواضيع طبية MeSH: Ligands* , Monte Carlo Method*, Molecular Dynamics Simulation/*standards, Humans
مستخلص: Flexible ligands often have multiple binding modes or bound conformations that differ by rotation of a portion of the molecule around internal rotatable bonds. Knowledge of these binding modes is important for understanding the interactions stabilizing the ligand in the binding pocket, and other studies indicate it is important for calculating accurate binding affinities. In this work, we use a hybrid molecular dynamics (MD)/nonequilibrium candidate Monte Carlo (NCMC) method to sample the different binding modes of several flexible ligands and also to estimate the population distribution of the modes. The NCMC move proposal is divided into three parts. The flexible part of the ligand is alchemically turned off by decreasing the electrostatics and steric interactions gradually, followed by rotating the rotatable bond by a random angle and then slowly turning the ligand back on to its fully interacting state. The alchemical steps prior to and after the move proposal help the surrounding protein and water atoms in the binding pocket relax around the proposed ligand conformation and increase move acceptance rates. The protein-ligand system is propagated using classical MD in between the NCMC proposals. Using this MD/NCMC method, we were able to correctly reproduce the different binding modes of inhibitors binding to two kinase targets-c-Jun N-terminal kinase-1 and cyclin-dependent kinase 2-at a much lower computational cost compared to conventional MD and umbrella sampling. This method is available as a part of the BLUES software package.
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معلومات مُعتمدة: R01 GM108889 United States GM NIGMS NIH HHS; R01 GM124270 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Ligands)
تواريخ الأحداث: Date Created: 20200215 Date Completed: 20201006 Latest Revision: 20240730
رمز التحديث: 20240730
مُعرف محوري في PubMed: PMC7325746
DOI: 10.1021/acs.jctc.9b01066
PMID: 32058713
قاعدة البيانات: MEDLINE
الوصف
تدمد:1549-9626
DOI:10.1021/acs.jctc.9b01066