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.

Abstract

Adhesion molecules are one of the most important proteins playing a major role in the regulationof cell migration, apoptosis, and survival. While adhesion molecules play a pivotal role inpreserving cellular matrix and tissue integrity, these molecules are also involved in thepathogenesis of cardiovascular diseases. The cell adhesion molecules are involved inatherosclerotic 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 majorgroups of the adhesion molecules involved in cardiovascular diseases.In the current study, computational analysis was performed to understand the effects of missensemutations on the structure and functions of the adhesion molecules. The computational studiescan lead to a better understanding of the role of single nucleotide polymorphic mutations on thefunctions of adhesion molecules. The single nucleotide polymorphism data of adhesion moleculeswas retrieved from gnomAD v2.1.1. Only the missense SNPs were selected, and the 3D proteinstructures of the adhesion molecules were retrieved from AlphaFold. The 3D protein structures ofthe adhesion molecules were mutated using USCF Chimera 1.14.The comparison of structural stability, structural change, and interaction with ligands wasperformed 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 withG179R and G727Q mutants of P-selectin (SELP) have also shown structural deviations ascompared to wild-type molecules. The R367C mutant of ICAM-1, P15L mutant of ICAM-3, andT756P mutant of SELP showed a significant change in the hydrogen bonding interactions withtheir respective ligands as compared to the wild-type protein interactions with a deviation from theoriginal binding free energies. No significant changes in the hydrogen bonding interactions wereobserved in the G179R and G727Q mutants of SELP.Moreover, phytochemicals data of several medicinal plants which were effective againstcardiovascular diseases was retrieved from the Indian Medicinal Plants, Photochemistry, andTherapeutics database. The molecular docking was performed to analyze the effects ofphytochemicals on adhesion molecules. The 3,29-Dihydroxyolean-12-en-28-oic acid, aphytochemical of the Panax ginseng plant was found to have an inhibitory effect on the activesites of adhesion molecules ICAM-1, ICAM-3, SELE, and SELP. Furthermore, the results of thisstudy can be tested experimentally to confirm the effect of adhesion molecule mutations on theonset of cardiovascular diseases and the role of 3,29-Dihydroxyolean-12-en-28-oic acid as ageneral drug for the treatment of diseases caused by mutant adhesion molecules.