Impact of loss-of-function variations of PCSK9 on LDLR interaction and dynamics: Implications for heart function

Integrative Biology research has deepened our understanding of various diseases particularly by elucidating the impact of nonsynonymous single nucleotide polymorphisms (nsSNPs) on disease and diagnosis. PCSK9 is an important cholesterol regulator, and genetic variations in this protein can influence cardiovascular risk. Loss-of-function (LOF) mutations in PCSK9 gene are linked to reduced plasma LDL cholesterol levels and prevent hypercholesterolemia. This study investigated the influence of nsSNPs of PCSK9 found in the Indian population to assess their impact on protein stability, dynamics and interaction with the LDL receptor (LDLR). Molecular dynamics Simulation were carried out on wild type PCSK9-LDLR and LOF PCSK9-LDLR complexes and revealed that R93C, N298D, and A511V mutations destabilize the PCSK9-LDLR complex, with A511V, a variant unique to the Indian population showing complete loss of all contacts with LDLR. Further analysis confirmed the structural instability of these LOF variants, suggesting their potential role in altered lipid regulation. The structure and dynamics of LDLR complex formation in wild type versus three LOF variants provides a basis for prediction of LOF of PCSK9 and may facilitate drug design and personalized low risk assessment for hypercholesterolemia leading to heart disease.