Integrated computational characterization of valosin-containing protein double-psi β-barrel domain: Insights into...

Valosin-containing protein (VCP) plays a crucial role in various cellular processes, yet the molecular mechanisms and structural dynamics of its double-psi β-barrel (DPBB) domain, particularly in human, remain insufficiently explored. While previous studies have characterized the VCP_DPBB domain in other organisms, such as thermoplasma acidophilum and methanopyrus kandleri, its evolutionary conservation, binding potential, and stability in human require further investigation. To address this gap, we first employed all-atom molecular dynamics (AAMD) simulations to examine the structural dynamics of the human VCP_DPBB domain. We also assessed its amino acid interaction energies, stability, folding enthalpy, evolutionary conservation, solubility, and crystallizability using various computational frameworks. Additionally, to uncover the plausible biological function, protein-peptide docking was performed to evaluate the interactions between the DPBB domain and the C-terminal gp78 peptide of the E3 ubiquitin ligase. Further, AAMD and coarse-grained molecular dynamics (CGMD) simulations explored the binding preferences, fluctuations, and stability of human VCP_DPBB-gp78 complexes. Our findings indicate that, while thermoplasma acidophilum VCP_DPBB-gp78 showed stronger initial binding, the human VCP_DPBB-gp78 complex exhibited superior stability, binding affinity, and more stabilizing interactions. This integrated analysis provides valuable insights into the evolutionary significance and functionality of the DPBB domain, with potential therapeutic implications for VCP-related diseases.