Delineating the impact of pathogenic mutations on the conformational dynamics of HDL’s vital protein ApoA1: a combined computational and molecular dynamic simulation approach

Abstract

Apolipoprotein A1 (ApoA1), is the important component of high‐density lipoproteins (HDL), that has key role in HDL biogenesis, cholesterol trafficking, and reverse cholesterol transport (RCT). Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) in ApoA1 have been linked to cardiovascular diseases and amyloidosis as they alter the protein’s native structure and function. Therefore in this study, we attempted to understand the molecular pathogenicity profile of nsSNPs of ApoA1 using various computational approaches. We used state-of-the-art computational methods to thoroughly investigate the 295 ApoA1 nsSNPs at sequence and structural levels. Seven nsSNPs (L13R, L84R, L84P, L99P, R173P, L187P, and L238P) out of 295 were classified as the most deleterious and destabilizing. In order to estimate the effect of such destabilizing mutations on the protein conformation, all-atom molecular dynamics simulations (MDS) of ApoA1 wild-type (WT), L99P and R173P for 100 ns, was carried out using GROMACS 5.0.1 package. The MD simulation investigation revealed significant structural alterations in L99P and R173P. In addition, they had changed principal component analysis and electrostatic surface potential, decreased structural compactness, and intramolecular hydrogen bonds, which supported the rationale underpinning ApoA1 dysfunction with such mutations. This work sheds light on ApoA1 dysfunction due to single amino acid alterations, and offers new insight into the molecular basis of ApoA1-related diseases progression.

Communicated by Ramaswamy H. Sarma

HIGHLIGHTS

• ApoA1 is a key HDL protein involved in RCT and HDL synthesis.

• Mutations in the ApoA1 protein can lead to defects in RCT and HDL biogenesis.

• In total 295nsSNPS of ApoA1 protein were studied using various computational approaches.

• Seven highly pathogenic and destabilizing mutations were found (L13R, L84R, L84P, L99P, R173P, L187P, and L238P).

• Further MD results showed L99P and R173P mutations in ApoA1 are highly destabilizing.

Keywords:

• Apolipoprotein A1 (ApoA1)
• amyloidosis
• high-density lipoproteins (HDL)
• reverse cholesterol transport (RCT)
• cardiovascular diseases
• molecular dynamic simulation (MDS)

Acknowledgments

The authors are grateful to the Vellore Institute of Technology, Vellore, India for providing the essential facilities to carry out this work.

Disclosure statement

The authors declare no conflict of interest for this work.

Author’s contributions

Aishwarya Sudam Bhale: Conceived the ideas, carried out literature survey, executed experiments, wrote, read and edited the manuscript. Krishnan Venkataraman: Conceived and provided the idea for the article, carried out literature survey, wrote, read, edited and communicated the manuscript to the journal.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.