Decoding molecular mechanism of species-selective targeting of fungal versus human HSP90 using multiple replica molecular dynamics simulations and binding free energy calculations

Abstract

As a highly evolutionarily conserved molecular chaperone, heat shock protein (HSP90), plays an important role in virulence traits, representing a therapeutic target for the treatment of fungal infections. The close evolutionary relationship between fungi and their human hosts poses a key challenge for the development of selective antifungal agents. In this work, molecular docking, multiple replica microsecond-based molecular dynamics (MD) simulations, and binding free energy calculations were performed to decode molecular mechanism of species-selective targeting of fungal versus human HSP90 triggered by the compound A11. MD simulations reveal that binding of compound A11 to human HSP90 nucleotide-binding domain (NBD) leads to obvious conformational changes relative to fungal HSP90 NBD. Binding free energy calculations show that the binding of compound A11 to fungal HSP90 NBD is stronger than that to human HSP90 NBD. Per residue-based free energy decomposition analysis was used to evaluate the inhibitor − residue interaction profile. The results efficiently identify the hot spot residues that play vital roles in favorable binding of compound A11 to fungal HSP90 NBD. This study is expected to provide a useful guidance for the development of selective inhibitors toward fungal HSP90. Communicated by Ramaswamy H. Sarma