Decoding Rac1′s dual role: A structural bioinformatics exploration of Plasmodium falciparum invasion of RBCs and treatment resistant hypertension

Rac1, a small GTPase, plays critical roles in Plasmodium falciparum invasion of red blood cells (RBCs) and activation of the Mineralocorticoid Receptor (MR) in a manner analogous to aldosterone, contributing to treatment resistance in hypertension therapies such as ARBs and ACEIs. Despite its importance, the structural basis of Rac1’s multifunctionality remains unclear. This study employs structural bioinformatics to elucidate Rac1’s conformational dynamics, key binding sites, and potential druggable regions. We employed a structural bioinformatics approach using the R-based Bio3D package to analyze Rac1′s structure (PDB: 1MH1). Sequence alignment and BLAST analysis identified 43 homologous structures (resolution ≤3 Å). Functional insights were obtained through structural annotation, binding site identification, and core conservation analysis. Principal Component Analysis (PCA) and Normal Mode Analysis (NMA) were used to explore conformational variability and dynamic behavior relevant to Rac1’s dual role. The analysis revealed critical residues (e.g., GLY 10, ASP 11, and LYS 116) and conserved structural motifs essential in Rac1′s for Plasmodium falciparum invasion and Mineralocorticoid Receptor (MR) interactions. PCA highlighted distinct conformational clusters highlighting Rac1’s structural adaptability, while NMA demonstrated dynamic flexibility in switch regions, providing insights into Rac1′s dual role in Plasmodium falciparum invasion of RBCs and MR activation. The conformational landscape captured key structural variations, explaining Rac1’s multifunctionality. This study provides a structural framework for Rac1, identifying key residues and dynamic properties underlying its multifunctionality. The findings offer potential therapeutic targets for overcoming ARB- and ACEI-related resistance. The computational pipeline is adaptable for studying other multifunctional proteins, advancing structural bioinformatics research.