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Synergizing multiresolution simulations, interface redesign, and hotspot mapping to decipher pathogenic

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Summary
This summary is machine-generated.

A mutation in valosin-containing protein (VCP/p97) disrupts its structure, impairing protein degradation pathways crucial for preventing diseases like IBMPFD and ALS.

Keywords:
Double-psi β-barrelInterface redesignMolecular dockingMolecular dynamics simulationUmbrella samplingValosin-containing protein

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Computational Biology

Background:

  • Valosin-containing protein (VCP/p97) is a key AAA+ ATPase regulating proteostasis through pathways like ER-associated degradation (ERAD).
  • Specific mutations, such as Arg95Gly (R95G), in VCP are linked to proteinopathies including inclusion body myopathy with Paget's disease and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS).

Purpose of the Study:

  • To elucidate the structural and dynamic changes caused by the R95G mutation in VCP.
  • To understand how these changes lead to VCP dysfunction and contribute to associated diseases.

Main Methods:

  • Integrated AlphaFold3 modeling, protein-peptide docking, and multiscale molecular dynamics (MD) simulations (all-atom, coarse-grained, umbrella sampling).
  • Utilized MM/PBSA and potential of mean force (PMF) analyses to assess binding thermodynamics.
  • Performed interface hotspot mapping to identify dynamic perturbations.

Main Results:

  • The R95G mutation destabilizes the VCP N-terminal domain's double-ψ β-barrel (DPBB) and disrupts inter-domain coupling.
  • This leads to conformational heterogeneity, hindering the recruitment of the gp78 cofactor.
  • Impaired binding thermodynamics and allosteric decoupling were observed, affecting the protein's interaction network.

Conclusions:

  • The R95G mutation initiates a cascade from local structural disruption to global functional impairment of VCP.
  • This study provides a computational framework for understanding VCP dysfunction in IBMPFD and ALS.
  • Findings can guide the development of therapeutic strategies to restore VCP function.