Non-active site mutations disturb the loop dynamics, dimerization, viral budding and egress of VP40 of the Ebola virus.
The first account of the dynamic features of the loop region of VP40 of the Ebola virus (EboV) using accelerated molecular dynamics (aMD) simulations is reported herein. Due to its major role in the Ebola life cycle, VP40 is considered a promising therapeutic target. The available experimental data on the N-terminal domain (NTD) loop indicates that mutations K127A, T129A and N130A demonstrate an unrecognized role for NTD-plasma membrane (PM) interaction for efficient VP40-PM localization, oligomerization, matrix assembly and egress. Despite experimental results, the molecular description of VP40 and the information it can provide still remain vague. Therefore, to gain further molecular insight into the effect of mutations on the loop region of VP40 and its effects on the overall protein conformation and VP40 dimerization, aMD simulations and post-dynamic analyses were employed for wildtype (WT) and mutant systems. The results showed significant variations in the presence of mutations as per RMSF, RMSD, Rg, PCA and distance calculations in comparison to the WT. These results could provide researchers with insight with regards to the conformational aspects concerning VP40 and its close relation to the experimental data. We believe that the results presented in this study will ultimately provide a useful understanding of the structural landscape of the loop region of VP40, which would contribute towards the discovery of novel EboV inhibitors.
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.
Marissa
M
Balmith
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 and Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt and College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, FAMU, Tallahassee, Florida 32307, USA.
Mahmoud E S
http://orcid.org/0000-0002-9209-7318
ME
Soliman
D000595:Amino Acid Sequence; D029043:Ebolavirus / Q000502:physiology*; D019142:Hemorrhagic Fever, Ebola / Q000821:virology; D006801:Humans; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D055503:Protein Multimerization; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000235:genetics*; D057074:Virus Release
C080981:VP40 protein, virus; D014763:Viral Matrix Proteins