Flap sub-domain dynamics of serine-threonine phosphatase (Stp1) of Staphylococcus aureus: an accelerated molecular dynamics simulation study

AbstractVancomycin and daptomycin are commonly used glycopeptide antibiotics to cure Gram-positive staphylococcal infections. The clinical isolates of mutant Staphylococcus aureusstrains, Methicillin-Resistant (MRSA) and Vancomycin-Resistant (VRSA), have developed resistance against these antibiotics. A recently discovered Serine/threonine phosphatase (Stp1) is an Mn+2containing protein at the active site with a flap sub-domain that participates in the phospho-signaling system of bacterial cell wall formation. The flap sub-domain probably regulates substrates recruitment and release with an extra Mn+2, possibly highly flexible as in the other homologous family of proteins. In this study, the flap sub-domain has been sampled with conventional and accelerated molecular dynamics (cMD and aMD) simulations to get other sub-optimal conformational states of the protein that are nearly impossible to observe through experimental methods. Trajectory analysis has shown that protein remained static in cMD while dynamic in aMD with RMSD of ∼2Å and ∼3Å, respectively. Accelerated MD has shown greater flexibility of ∼4 Å in the flap sub-domain, while cMD only captured a deviation of ∼ 2 Å. Later, the dynamic cross-correlation map (DCCM) confirmed that the flap sub-domain is significantly more flexible than the other part of the structure, indicating its role in substrate regulation. Secondary structure transition in the flap sub-domain, i.e. 3-10 helix and turn (PRO159 - ILE163) region of the flap sub-domain shifted into α-helix, which is a more stable structure. Further, the trajectory has been clustered, and conformational states extracted, which may be exploited in structure-based antibiotics discovery.Communicated by Ramaswamy H. Sarma