Dielectric Relaxation in an Enzyme Active Site: Molecular Dynamics Simulations Interpreted with a Macroscopic Continuum Model

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• 作者：Georgios Archontis and Thomas Simonson
• 刊名：Journal of the American Chemical Society
• 出版年：2001
• 出版时间：November 7, 2001
• 年：2001
• 卷：123
• 期：44
• 页码：11047 - 11056
• 全文大小：218K
• 年卷期：v.123,no.44(November 7, 2001)
• ISSN：1520-5126

文摘

Dielectric relaxation plays an important role in many chemical processes in proteins, including acid-base titration, ligand binding, and charge transfer reactions. Its complexity makes experimental characterizationdifficult, and so, theoretical approaches are valuable. The comparison of molecular dynamics free energysimulations with simpler models such as a dielectric continuum model is especially useful for obtainingqualitative insights. We have analyzed a charge insertion process that models deprotonation or mutation of animportant side chain in the active site of the enzyme aspartyl-tRNA synthetase. Complexes with the substrateaspartate and the analogue asparagine were studied. The resulting dielectric relaxation was found to involveboth ligand and side chain rearrangements in the active site and to account for a large part of the overallcharging free energy. With the continuum model, charge insertion is performed along a two-step pathway:insertion into a static environment, followed by relaxation of the environment. These correspond to differentphysical processes and require different protein dielectric constants. A low value of ~1 is needed for the staticstep, consistent with the parametrization of the molecular mechanics charge set used. A value of 3-6 (dependingon the exact insertion site and the nature of the ligand) is needed to describe the dielectric relaxation step. Thismoderate value indicates that, for this system, the local protein polarizability in the active site is within atmost a factor of 2 of that expected at nonspecific positions in a protein interior.