Homology modelling and molecular dynamics simulations of a protein serine/threonine phosphatase stp1 in Staphylococcus aureus N315: a potential drug target

摘要

The prevalence of methicillin-resistant Staphylococcus aureus and vanomycin intermediate S. aureus infections is on the rise, globally. This poses a huge challenge due to limited therapeutic options and the limited number of bacterial-specific drug targets available for due conservation with the human host. A serine/threonine phosphatase/kinase stp1/stk1 phospho-signalling system in S. aureus, which is just beginning to be understood, has been shown to be of importance in virulence and susceptibility to glycopeptide antibiotics. In this study, 3D structure of stp1 (clinical strain of S. aureus N315) was predicted using a homology modelling tool MODELLER. The validation of the predicted model was done using various tools such as PROCHECK, ERRAT, VERIFY-3D and ProSA. Molecular dynamics (MD) study was carried out using GROMACS to refine the least energy model generated from MODELLER9v11 and it was compared with the template. The template used was the crystal structure of serine/threonine phosphatase stp1 in Streptoccocus agalactiae (Protein Data Bank ID: 2PK0) with 38% identity with the query. Various validation tools showed the quality of the model generated using MODELLER. PROCHECK predicted 100% residues in the allowed region, ERRAT with overall quality factor of 76.47, VERIFY-3D with average score of >0.2 in 81.78% of residues, WHATIF with packaging quality score of >-5 for all residues and ProSA with Z-score of -7.02. MD simulation of the protein showed some fluctuations in the aqueous environment and changes in the ligand binding residues after simulation. The availability of the 3D-structural information of a viable drug target in S. aureus stp1 is expected to facilitate structure-activity relationship and interactions with proteins.