Computational insights into Candida albicans Malate synthase: impact of cofactor and substrates on enzyme conformation and tunnel formation.

interventions to better understand CaMLS1 functional architecture thereby aiding in design of the therapeutic drug agents. In this study, computational approaches such as MD simulations, correlations studies and binding affinity analysis were employed to delineate the structural dynamics and to investigate the interactions of cofactors and substrates with CaMLS1. From the results, template-based 3D modeling revealed that CaMLS1 has three domains: N-terminal, TIM-barrel and C-terminal domain, of which TIM-barrel found to be dynamic through MD studies. However, substrates (GOXL and ACOA) binding to CaMLS1 markedly reduced this dynamism, indicating the stability of the complex. The binding free energy calculations of the complex showed that ACOA binds with notably higher affinity (-921 kJ/mol) than GOXL (-6 kJ/mol), consistent with previous observations reported in literature. Furthermore, presence of cofactors and substrates modulated the tunnel availability at the active site, thereby affecting substrate's access and product release through changes in the enzyme's conformational dynamics. These findings offer a scope for the design of molecules targeting the CaMLS1 for antifungal therapy.