In-Silico analysis of the structural and functional impact of SNPs in adhesion molecules associated with cardiovascular disease and the effect of potential phytochemicals on these molecules.

Authors

  • Mureed Hussain Department of Life Sciences, University of Management and Technology, Lahore, Pakistan. & Agha Khan University, Karachi.
  • Muhammad Perwaiz Iqbal Department of Life Sciences, University of Management and Technology, Lahore, Pakistan. & Agha Khan University, Karachi.
  • Koukab Imran Department of Life Sciences, University of Management and Technology, Lahore, Pakistan.
  • Rana Muhammad Mateen Department of Life Sciences, University of Management and Technology, Lahore, Pakistan.

DOI:

https://doi.org/10.52700/jmmg.v5i1.144

Abstract

Adhesion molecules are one of the most important proteins playing a major role in the regulation
of cell migration, apoptosis, and survival. While adhesion molecules play a pivotal role in
preserving cellular matrix and tissue integrity, these molecules are also involved in the
pathogenesis of cardiovascular diseases. The cell adhesion molecules are involved in
atherosclerotic plaque progression, deposition of fibrotic tissue, and thrombus formation. Selectins
-E and -P and members of the immunoglobulin superfamily ICAM-1 and ICAM-3 are the major
groups of the adhesion molecules involved in cardiovascular diseases.
In the current study, computational analysis was performed to understand the effects of missense
mutations on the structure and functions of the adhesion molecules. The computational studies
can lead to a better understanding of the role of single nucleotide polymorphic mutations on the
functions of adhesion molecules. The single nucleotide polymorphism data of adhesion molecules
was retrieved from gnomAD v2.1.1. Only the missense SNPs were selected, and the 3D protein
structures of the adhesion molecules were retrieved from AlphaFold. The 3D protein structures of
the adhesion molecules were mutated using USCF Chimera 1.14.
The comparison of structural stability, structural change, and interaction with ligands was
performed between the wild-type and mutant adhesion molecules by several bioinformatics tools.
The R458W mutant of ICAM-1 was found to be destabilizing the structure of the protein.
Similarly, the V88M mutant of ICAM-3 and H468Y mutant of E-selectin (SELE), along with
G179R and G727Q mutants of P-selectin (SELP) have also shown structural deviations as
compared to wild-type molecules. The R367C mutant of ICAM-1, P15L mutant of ICAM-3, and
T756P mutant of SELP showed a significant change in the hydrogen bonding interactions with
their respective ligands as compared to the wild-type protein interactions with a deviation from the
original binding free energies. No significant changes in the hydrogen bonding interactions were
observed in the G179R and G727Q mutants of SELP.
Moreover, phytochemicals data of several medicinal plants which were effective against
cardiovascular diseases was retrieved from the Indian Medicinal Plants, Photochemistry, and
Therapeutics database. The molecular docking was performed to analyze the effects of
phytochemicals on adhesion molecules. The 3,29-Dihydroxyolean-12-en-28-oic acid, a
phytochemical of the Panax ginseng plant was found to have an inhibitory effect on the active
sites of adhesion molecules ICAM-1, ICAM-3, SELE, and SELP. Furthermore, the results of this
study can be tested experimentally to confirm the effect of adhesion molecule mutations on the
onset of cardiovascular diseases and the role of 3,29-Dihydroxyolean-12-en-28-oic acid as a
general drug for the treatment of diseases caused by mutant adhesion molecules.

Published

2024-04-30