title: Exploring transition pathway and free-energy profile of large-scale protein conformational change by combining normal mode analysis and umbrella sampling molecular dynamics.
abstract: Large-scale conformational changes of proteins are usually associated with the binding of ligands. Because the conformational changes are often related to the biological functions of proteins, understanding the molecular mechanisms of these motions and the effects of ligand binding becomes very necessary. In the present study, we use the combination of normal-mode analysis and umbrella sampling molecular dynamics simulation to delineate the atomically detailed conformational transition pathways and the associated free-energy landscapes for three well-known protein systems, viz., adenylate kinase (AdK), calmodulin (CaM), and p38α kinase in the absence and presence of respective ligands. For each protein under study, the transient conformations along the conformational transition pathway and thermodynamic observables are in agreement with experimentally and computationally determined ones. The calculated free-energy profiles reveal that AdK and CaM are intrinsically flexible in structures without obvious energy barrier, and their ligand binding shifts the equilibrium from the ligand-free to ligand-bound conformation (population shift mechanism). In contrast, the ligand binding to p38α leads to a large change in free-energy barrier (ΔΔG ≈ 7 kcal/mol), promoting the transition from DFG-in to DFG-out conformation (induced fit mechanism). Moreover, the effect of the protonation of D168 on the conformational change of p38α is also studied, which reduces the free-energy difference between the two functional states of p38α and thus further facilitates the conformational interconversion. Therefore, the present study suggests that the detailed mechanism of ligand binding and the associated conformational transition is not uniform for all kinds of proteins but correlated to their respective biological functions.
authors.affiliation: Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai, 201203, China.
authors.forename: Jinan
authors.initials: J
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shao
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Xu
authors.forename: Yingtao
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yang
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Cossins
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Jiye
authors.initials: J
authors.lastname: Shi
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000263:Adenylate Kinase / Q000737:chemistry* / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013816:Thermodynamics; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002147:Calmodulin; D048051:p38 Mitogen-Activated Protein Kinases; D000263:Adenylate Kinase