The structural basis of acid resistance in Mycobacterium tuberculosis: insights from multiple pH regime molecular dynamics simulations

The dormant Mycobacterium tuberculosis is evolved to develop the tolerance against the acidification of phagolysosome by the action of gamma interferon. The molecular mechanism responsible for the development of the resistance towards the acidic conditions in M. tuberculosis is not fully understood. Therefore, the current analysis was performed which studies the mechanism of acid tolerance by correlating the alteration in the protonation state of conserved residues in virulent proteins with changes in their folding states. The pH dependencies of proteins were studied using an efficient computational scheme which enables the understanding of their conformational behavior by molecular dynamics (MD) simulations. The adopted methodology involves cyclically updating of the ionization states of titrable residues in the studied proteins with conventional MD steps, which were applied to the newly generated ionization configuration. Significant pH-dependent protein structural stability parameters consistent with the changes of the protonation states of conserved residues were observed. Among the studied proteins, the peptidoglycan binding protein ompATB, carboxylesterase LipF and two-component systems' transcriptional regulator PhoP showed highest structural conservation in the observed acidic pH range throughout the course of MD simulations. The current study provides a better understanding of acid tolerance mechanisms present in M. tuberculosis and can facilitate the drug development strategies against the dormant protein targets. Communicated by Ramaswamy H. Sarma