Insights into Mcl-1 Conformational States and Allosteric Inhibition Mechanism from Molecular Dynamics Simulations, Enhanced Sampling, and Pocket Crosstalk Analysis

Autor:	Ronan Bureau, Mohammed Benabderrahmane, Jana Sopkova-de Oliveira Santos, Anne Sophie Voisin-Chiret
Rok vydání:	2020
Předmět:	Protein Conformation Chemistry Entropy General Chemical Engineering Allosteric regulation General Chemistry Molecular Dynamics Simulation Library and Information Sciences Computer Science Applications Crosstalk (biology) Molecular dynamics Allosteric Regulation Biophysics Protein Binding
Zdroj:	Journal of Chemical Information and Modeling. 60:3172-3187
ISSN:	1549-960X 1549-9596
DOI:	10.1021/acs.jcim.0c00315
Popis:	In this study, we explored the structural dynamics of Mcl-1, an anti-apoptotic protein. On the basis of structural ensembles, the essential dynamics was extracted and showed two major axes of variability: a breathing motion at the binding interface and a correlated motion through the internal loops. A free energy surface characterizing the breathing motion at the binding interface was generated and suggested an equilibrium between a closed conformation and a "ready to bind" conformation as the predominant states of Mcl-1 in solution. Moreover, the analysis of the dynamics along the internal loops revealed a hidden communication network of transient and cryptic pockets controlling the allosteric inhibition of Mcl-1. A detailed model joining the pocket crosstalk and salt bridge networks along the internal loops was proposed and allowed us to shed light on the key interactions governing Mcl-1's allosteric inhibition.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::42bc3857ca4d98d7ed05e02aa5e0498f https://doi.org/10.1021/acs.jcim.0c00315 Zobrazit plný text záznamu