title: Analysis of Flexibility and Hotspots in Bcl-xL and Mcl-1 Proteins for the Design of Selective Small-Molecule Inhibitors.
abstract: Although Bcl-xL and Mcl-1, two antideath Bcl-2 members, have similar, flexible binding sites, they can achieve high binding selectivity to endogenous binding partners and synthetic small-molecule inhibitors. Here, we employed molecular dynamic (MD) simulations and hotspot analysis to investigate the conformational flexibility of these proteins and their binding hotspots at the binding sites. Backbone flexibility analyses indicate that the highest degree of flexibility in Mcl-1 is the α4 helical segment as opposed to the α3 helix in Bcl-xL among four helical segments in their binding sites. Furthermore, common and unique binding hotspots at both proteins were identified using small-molecule probes. These analyses can aid the design of potent and specific small-molecule inhibitors for these proteins.
authors.affiliation: Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0934, United States.
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-0934, United States.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
keywords: Bcl-xL; Mcl-1; backbone flexibility; binding selectivity; cosolvent molecular dynamics simulation