科研之友
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摘要
Allostery is a general phenomenon in proteins whereby a perturbation at one site reverberates into a functional change at another one, through modulation of its conformational dynamics. Herein, we address the problem of how the molecular signal encoded by a ligand is differentially transmitted through the structures of two homologous PDZ proteins: PDZ2, which responds to binding with structural and dynamical changes in regions distal from the ligand site, and PDZ3, which is characterized by less-intense dynamical variations. We use novel methods of analysis of MD simulations in the unbound and bound states to investigate the determinants of the differential allosteric behavior of the two proteins. The analysis of the correlations between the redistribution of stabilization energy and local fluctuation patterns highlights the nucleus of residues responsible for the stabilization of the 3D fold, the stability core, as the substructure that defines the difference in the allosteric response: in PDZ2, it undergoes a consistent dynamic and energetic reorganization, whereas in PDZ3, it remains largely unperturbed. Specifically, we observe for PDZ2 a significant anticorrelation between the motions of distal loops and residues of the stability core and differences in the correlation patterns between the bound and unbound states. Such variation is not observed in PDZ3, indicating that its energetics and internal dynamics are less affected by the presence/absence of the ligand. Finally, we propose a model with a direct link between the modulation of the structural, energetic and dynamic properties of a protein, and its allosteric response to a perturbation.
- 出版日期2014-12
