title: Free-Energy Landscape of Protein-Ligand Interactions Coupled with Protein Structural Changes.
abstract: Protein-ligand interactions are frequently coupled with protein structural changes. Focusing on the coupling, we present the free-energy surface (FES) of the ligand-binding process for glutamine-binding protein (GlnBP) and its ligand, glutamine, in which glutamine binding accompanies large-scale domain closure. All-atom simulations were performed in explicit solvents by multiscale enhanced sampling (MSES), which adopts a multicopy and multiscale scheme to achieve enhanced sampling of systems with a large number of degrees of freedom. The structural ensemble derived from the MSES simulation yielded the FES of the coupling, described in terms of both the ligand's and protein's degrees of freedom at atomic resolution, and revealed the tight coupling between the two degrees of freedom. The derived FES led to the determination of definite structural states, which suggested the dominant pathways of glutamine binding to GlnBP: first, glutamine migrates via diffusion to form a dominant encounter complex with Arg75 on the large domain of GlnBP, through strong polar interactions. Subsequently, the closing motion of GlnBP occurs to form ligand interactions with the small domain, finally completing the native-specific complex structure. The formation of hydrogen bonds between glutamine and the small domain is considered to be a rate-limiting step, inducing desolvation of the protein-ligand interface to form the specific native complex. The key interactions to attain high specificity for glutamine, the "door keeper" existing between the two domains (Asp10-Lys115) and the "hydrophobic sandwich" formed between the ligand glutamine and Phe13/Phe50, have been successfully mapped on the pathway derived from the FES.
authors.affiliation: Graduate School of Medical Life Science, Yokohama City University , 1-7-29 Suehirocho, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Kei
authors.identifier: 0000-0002-5025-6579
authors.initials: K
authors.lastname: Moritsugu
authors.affiliation: Graduate School of Agricultural and Life Sciences, The University of Tokyo , 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Terada
authors.affiliation: Graduate School of Medical Life Science, Yokohama City University , 1-7-29 Suehirocho, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kidera
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry*; D005973:Glutamine / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D002352:Carrier Proteins; D008024:Ligands; C037853:glutamine transport proteins; D005973:Glutamine