Structural Basis for M2-2-MAVS Proteins Interaction in Human Metapneumovirus (HMPV): Exploring the Immune Evasion Mechanism Through Biomolecular Modeling, Structural Mutagenesis and Classical Simulations.

Abstract

Human metapneumovirus (HMPV) was first discovered in the Netherlands in 2001 and is now considered one of the most important contributors to viral respiratory diseases. It is often asymptomatic in healthy adults but can cause serious illness among immunocompromised or older patients. In response to the infection, the viral immune evasion mechanism remains a key approach for evading the immune response. In hMPV, the M2-2 protein interacts with the hMAVS protein to evade the immune response. It is essential to understand how the mechanism takes place for designing potential therapeutic agents. Thus, herein, we provide structural mechanisms of the interaction between M2-2 and MAVS through biomolecular interactions, in silico alanine scanning, and classical simulation approaches (repeated). We selected the HADDOCK-generated complex from the docking results, leaving the others from ZDOCK, Cluspro, and PyDOCK. Using alanine scanning, 18 interface residues were identified consensually, among which 8 residues, P29A, E30A, M31A, W33A, E37A, Q39A, E40A, and K48A, significantly affected the binding and were selected for the subsequent analysis. The docking results of these alanine mutants reported a significant reduction in the HADDOCK score, electrostatic energies, and vdW forces. Moreover, the stability of these mutations has been significantly compromised during simulation, while the total binding free energy also corroborates with the docking scores. From the detailed hydrogen-bond analysis, the interactions were significantly reduced in the mutants' complexes compared to the wild type, suggesting that alanine substitutions weaken the M2-1 and MAVS interaction by disrupting its finely tuned interaction network, highlighting potential vulnerabilities in its binding mechanism. The dissociation constant (K_d) results further validated discrepancies in the binding strength caused by the alanine substitutions. This study provides insights into the immune evasion mechanism of the hMPV virus and provides a basis for therapeutic development.