Characterization of the conformational dynamics between the closed and open states of M2-1 protein from hRSV and hMPV viruses

The Pneumovirus family (Pneumoviridae) includes human Respiratory Syncytial Virus (hRSV) and human Metapneumovirus (hMPV). These viruses are the leading causes of acute respiratory diseases, such as pneumonia and bronchiolitis, in children worldwide. They are also major contributors to respiratory morbidity in the elderly, immunocompromised individuals, and those with cardiorespiratory diseases. Although similar in three-dimensional structure, the crystal structure of hMPV M2-1 tetramer reveals an asymmetric unit with one of the protomers adopting an open conformation compared to the crystal structure of hRSV M2-1. This new structural possibility leads us to a perspective where conformational changes result in a dynamic equilibrium between open and closed conformations, aligning with the characteristics of the M2-1 protein, which acts on multiple fronts within the viral system, each compatible with specific functions. In this study, we employed simplified models to perform molecular dynamics simulations of the M2-1 protein from hRSV and hMPV viruses. This modeling approach is robust and captures the thermodynamic properties of the system, enabling the adjustment of the potential for studying transitions between different possible conformations. Starting from the open conformation, we achieved conformational transitions to the closed state, enabling detailed analysis, such as assessing the energy barrier during the transition, identifying key residues and regions involved in the transition, as well as the main energetic differences between hMPV and hRSV. The next steps of this study involve refining the models by incorporating more structural information, along with the search and design of ligands that can directly influence conformational transitions.