jp4105129_si_003.mpg (4.65 MB)
Exploring Transition Pathway and Free-Energy Profile of Large-Scale Protein Conformational Change by Combining Normal Mode Analysis and Umbrella Sampling Molecular Dynamics
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posted on 2014-01-09, 00:00 authored by Jinan Wang, Qiang Shao, Zhijian Xu, Yingtao Liu, Zhuo Yang, Benjamin
P. Cossins, Hualiang Jiang, Kaixian Chen, Jiye Shi, Weiliang ZhuLarge-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.