title: VP40 of the Ebola Virus as a Target for EboV Therapy: Comprehensive Conformational and Inhibitor Binding Landscape from Accelerated Molecular Dynamics.
abstract: The first account of the dynamic features of the loop region of VP40 of the Ebola virus was studied using accelerated molecular dynamics simulations and reported herein. Among the proteins of the Ebola virus, the matrix protein (VP40) plays a significant role in the virus lifecycle thereby making it a promising therapeutic target. Of interest is the newly elucidated N-terminal domain loop region of VP40 comprising residues K127, T129, and N130 which when mutated to alanine have demonstrated an unrecognized role for N-terminal domain-plasma membrane interaction for efficient VP40-plasma membrane localization, oligomerization, matrix assembly, and egress. The molecular understanding of the conformational features of VP40 in complex with a known inhibitor still remains elusive. Using accelerated molecular dynamics approaches, we conducted a comparative study on VP40 apo and bound systems to understand the conformational features of VP40 at the molecular level and to determine the effect of inhibitor binding with the aid of a number of post-dynamic analytical tools. Significant features were seen in the presence of an inhibitor as per molecular mechanics/generalized born surface area binding free energy calculations. Results revealed that inhibitor binding to VP40 reduces the flexibility and mobility of the protein as supported by root mean square fluctuation and root mean square deviation calculations. The study revealed a characteristic "twisting" motion and coiling of the loop region of VP40 accompanied by conformational changes in the dimer interface upon inhibitor binding. We believe that results presented in this study will ultimately provide useful insight into the binding landscape of VP40 which could assist researchers in the discovery of potent Ebola virus inhibitors for anti-Ebola therapies.
authors.affiliation: Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
authors.forename: Marissa
authors.initials: M
authors.lastname: Balmith
authors.affiliation: Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa. soliman@ukzn.ac.za.
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D029043:Ebolavirus; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy; D006801:Humans; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011485:Protein Binding; D055503:Protein Multimerization; D013816:Thermodynamics; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; C080981:VP40 protein, virus; D014763:Viral Matrix Proteins
keywords: Accelerated molecular dynamics; Binding free energy; Dimerization; Ebola virus; Loop region