Exploring the mechanism how Marburg virus VP35 recognizes and binds dsRNA by molecular dynamics simulations and free energy calculations

Abstract

Filoviruses often cause terrible infectious disease which has not been successfully dealt with pharmacologically. All filoviruses encode a unique protein termed VP35 which can mask doubled-stranded RNA to deactivate interferon. The interface of VP35-dsRNA would be a feasible target for structure-based antiviral agent design. To explore the essence of VP35-dsRNA interaction, molecular dynamics simulation combined with MM-GBSA calculations were performed on Marburg virus VP35-dsRNA complex and several mutational complexes. The energetic analysis indicates that nonpolar interactions provide the main driving force for the binding process. Although the intermolecular electrostatic interactions play important roles in VP35-dsRNA interaction, the whole polar interactions are unfavorable for binding which result in a low binding affinity. Compared with wild type VP35, the studied mutants F228A, R271A, and K298A have obviously reduced binding free energies with dsRNA reflecting in the reduction of polar or nonpolar interactions. The results also indicate that the loss of binding affinity for one dsRNA strand would abolish the total binding affinity. Three important residues Arg271, Arg294, and Lys298 which makes the largest contribution for binding in VP35 lose their binding affinity significantly in mutants. The uncovering of VP35-dsRNA recognition mechanism will provide some insights for development of antiviral drug.

Molecular basis of the recognition of arachidonic acid by cytochrome P450 2E1 along major access tunnel

“…MD simulations for both AA‐bound and dodecanoic analog‐bound complex structures including energy minimization were carried out using AMBER 11 software package and the ff99SB force field . Another substrate‐free form of CYP2E1 was also simulated to find the possible tunnels from the active site to the surface of the enzyme in the absence of the substrates.…”

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview

“…Specifically, Xue et al studied a UP35 protein (from filoviruses) complexed with dsRNA, and performed MM-GBSA free-energy calculations (see section 3.2.8 ) to identify residues responsible for the protein’s RNA affinity. 1086 Allen et al studied a B2 protein/dsRNA complex from the Nodamura Virus. 1087 Their study described the dynamics of the wild-type protein/RNA complex and that of complexes with several mutant proteins.…”

Recent advances in marburgvirus research

“…In regard to its function as a suppressor of type I IFN production, MARV VP35 seems to be less efficient than its EBOV homolog 59– 61 . This difference might be due to differences in the binding modes and affinities of EBOV and MARV VP35 proteins to double-stranded RNA, potentially impacting the inhibition of downstream antiviral pathways 59, 60, 62 . Interestingly, compared with MARV VP35, RAVV VP35 seems to be more efficient in suppressing type I IFN production 61 .…”