understanding the conformational dynamics and flexibility of mip and fkbp12 complexed with rapamycin, and role of water in protein-ligand binding: a molecular dynamics simulation study

Macrophage infectivity potentiator (mip) proteins have been identified in some pathogens, including both bacterial and eukaryotic species. these proteins are among the virulence factors that are essential for host cell infection and pathogen replication; therefore, they are potential candidates for new antimicrobial drug development. the ppiase (cis-trans peptidyl-prolyl isomerase) domain of mip exhibits a strong similarity to that of human fkbp12, making the search for non-immunosuppressive fkbp inhibitors more challenging. the aim of this study is to reveal the conformational differences between mip and fkbp12 in their unbound and bound states with rapamycin, and the role of water in protein-ligand interactions. molecular dynamics simulations (md simulations), dihedral angle principal component analysis, coordination propensities, analysis of hydrogen bonds and hydrophobic protein-ligand interactions were performed. the md simulations reveal that the both proteins demonstrate a larger dynamic field with more atomic fluctuations and are less stable in the unbound conditions. compared to fkbp12, mip exhibited a notable conformational difference between its bound and unbound states, primarily due to residue y109 shifting toward the binding cavity. moreover, a single water molecule was found mediating mip-rapamycin interactions. this water-mediated interaction may play a special role in stabilizing the complex. molecular dynamics with explicit solvent models have proven essential for understanding interactions at an atomistic level. the studies reveal the importance of considering water effects for the design of selective inhibitors for mip.