Dynamics of the personalities of PCSK9 on missense variants (rs505151 and rs562556) from elderly cohort studies in Brazil

Abstract

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptors (LDLR). Gain-of-function (GOF) variants of PCSK9 significantly affects lipid metabolism leading to coronary artery disease (CAD), owing to the raising the plasma low-density lipoprotein (LDL). Considering the public health matter, large-scale genomic studies have been conducted worldwide to provide the genetic architecture of populations for the implementation of precision medicine actions. Nevertheless, despite the advances in genomic studies, non-European populations are still underrepresented in public genomic data banks. Despite this, we found two high-frequency variants (rs505151 and rs562556) in the ABraOM databank (Brazilian genomic variants) from a cohort SABE study conducted in the largest city of Brazil, São Paulo. Here, we assessed the structural and dynamical features of these variants against WT through a molecular dynamics study. We sought fundamental dynamical interdomain relations through Perturb Response Scanning (PRS) and we found an interesting change of dynamical relation between prodomain and Cysteine-Histidine-Rich-Domain (CHRD) in the variants. The results highlight the pivotal role of prodomain in the PCSK9 dynamic and the implications for the development of new drugs depending on patient group genotype.

Keywords:

• PCSK9 variants
• Prodomain
• CHRD
• Molecular Dynamics
• Perturb Response Scanning (PRS)

Author contributions statement

V.G.L, G.M.F and L.M.M.D. design in silico experiments and analysis. V.F.O., M.S.N., M.H.H, and G.M.F helped with the discussion and writing. M.S.N., M.H.H, and G.M.F contributed to resources and overall study supervision. All authors prepared and reviewed the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Competing interests

The authors declare no competing interests.

Additional information

Funding

In Brazil, this study was supported by FAPESP (Grant # 2016/12899-6, 2018/11917-6, 2020/06490-3, and 2021/11205-9). VFO, VGL and GMF are a recipient of a fellowship from FAPESP, Brazil. We acknowledge Desmond Molecular Dynamics System, version 6.4, D. E. Shaw Research, New York, NY for making this software available for academics.