In Silico Insights into Protein-protein Interaction Disruptive Mutations in the PCSK9-LDLR complex.

ABSTRACT: Gain-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) lead to reduced uptake of LDL (low density lipoprotein) cholesterol and, therefore, increased plasma LDL levels. However, the mechanism by which these mutants reduce LDL reuptake is not fully understood. Here, we have used molecular dynamics simulations, MM/PBSA (Molecular Mechanics/Poisson-Boltzmann Surface Area) binding affinity calculations, and residue interaction networks, to investigate the protein-protein interaction (PPI) disruptive effects of two of PCSK9's gain-of-function mutations, Ser127Arg and Asp374Tyr on the PCSK9 and LDL receptor complex. In addition to these PPI disruptive mutants, a third, non-interface mutation (Arg496Trp) is included as a positive control. Our results indicate that Ser1

SUBMITTER: Martin WR 

PROVIDER: S-EPMC7084799 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature