期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 133, 期 18, 页码 7075-7083出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja1116233
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资金
- Korean Government (MOEHRD) [KRF-2008-313-C00404]
- SRC Research Center for Women's Diseases of Sookmyung Women's University
- KISTI Supercomputing Center
Protein engineering method to study the mutation effects on muscle acylphosphatase (AcP) has been actively applied to describe kinetics and thermodynamics associated with AcP aggregation as well as folding processes. Despite the extensive mutation experiments, the molecular origin and the structural motifs for aggregation and folding kinetics as well as thermodynamics of AcP have not been rationalized at the atomic resolution. To this end, we have investigated the mutation effects on the structures and thermodynamics for the aggregation and folding of AcP by using the combination of fully atomistic, explicit-water molecular dynamics simulations, and three-dimensional reference interaction site model theory. The results indicate that the A30G mutant with the fastest experimental aggregation rate displays considerably decreased alpha l-helical contents as well as disrupted hydrophobic core compared to the wild-type AcP. Increased solvation free energy as well as hydrophobicity upon A30G mutation is achieved due to the dehydration of hydrophilic side chains in the disrupted alpha l-helix region of A30G. In contrast, the Y91Q mutant with the slowest aggregation rate shows a non-native H-bonding network spanning the mutation site to hydrophobic core and alpha l-helix region, which rigidifies the native state protein conformation with the enhanced alpha l-helicity. Furthermore, Y91Q exhibits decreased solvation free energy and hydrophobicity compared to wild type due to more exposed and solvated hydrophilic side chains in the alpha l-region. On the other hand, the experimentally observed slower folding rates in both mutants are accompanied by decreased helicity in alpha 2-helix upon mutation. We here provide the atomic-level structures and thermodynamic quantities of AcP mutants and rationalize the structural origin for the changes that occur upon introduction of those mutations along the AcP aggregation and folding processes.
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