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首页> 外文期刊>The journal of physical chemistry, B. Condensed matter, materials, surfaces, interfaces & biophysical >Towards Accurate Ab Initio QM/MM Calculations of Free-Energy Profiles of Enzymatic Reactions
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Towards Accurate Ab Initio QM/MM Calculations of Free-Energy Profiles of Enzymatic Reactions

机译：进行精确的从头算起QM / MM计算酶反应自由能图

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Reliable studies of enzymatic reactions by combined quantum mechanical/molecular mechanics(QM/MM)approaches,with an ab initio description of the quantum region,presents a major challenge to computational chemists.The main problem is the need for a large amount of computer time to evaluate the QM energy,which in turn makes it extremely challenging to perform proper configurational sampling.This work presents major progress toward the evaluation of ab initio QM/MM free-energy surfaces and activation free energies of reactions in enzymes and in solutions.This is done by exploiting our previous idea of using the empirical valence bond(EVB)method as a reference potential and then using the linear response approximation(LRA)approach to evaluate the free energies of transfer from the EVB to the QM/MM surfaces in the reactant and product state.However,the new crucial step involves the use of a constraint at the transition state that fixes the system at a given value of the reaction coordinate and allows us to use the LRA at the transition state.The advance offered by the present approach is particularly significant because it evaluates the free energy associated with both the substrate and the solvent motions.This evaluation appeared to be a relatively simple task once one uses a classical reference potential.The main problem has been using the reference potential for the evaluation of the free-energy contributions associated with the solute motions where the difference between the reference EVB potential and the QM/MM potential can be large.The present refinement finally allows us to overcome the problems with the solute fluctuations and therefore to obtain,for the first time,a free-energy barrier that reflects the solute entropy properly.Thus,we present a way to evaluate the complete QM/MM activation free energy with an equal footing treatment of the solute and the solvent.This provides a general consistent and effective strategy for evaluating the QM/MM activation free energies in proteins and in solution.Our advance allows one to explore consistently various mechanistic and catalytic proposals while using ab initio(ai)QM/MM approaches.
机译：结合量子力学/分子力学（QM / MM）方法对酶促反应进行可靠的研究，并从头开始描述量子区，这对计算化学家构成了重大挑战。主要问题是需要大量的计算机时间评估QM能量，这反过来给进行正确的结构取样带来极大挑战。这项工作为评估从头开始的QM / MM自由能表面以及酶和溶液中反应的活化自由能提供了重大进展。通过利用我们先前的经验价键（EVB）方法作为参考电势，然后使用线性响应近似（LRA）方法来评估从EVB传递到QM / MM表面中的自由能的方法来完成但是，新的关键步骤涉及在过渡状态下使用约束条件，将系统固定在给定的反应坐标值下并允许我们在过渡状态下使用LRA。本方法的进步特别重要，因为它可以评估与底物和溶剂运动相关的自由能。这种评估似乎是一项相对简单的任务，主要问题是使用参考电势来评估与溶质运动相关的自由能贡献，其中参考EVB电势与QM / MM电势之差可能很大。使我们能够克服溶质波动带来的问题，因此首次获得了能正确反映溶质熵的自由能垒。因此，我们提出了一种方法来评估完整的QM / MM活化自由能。对溶质和溶剂进行均等的处理，这为评估QM / MM无活化e我们的先进技术使人们能够在使用从头开始（ai）QM / MM方法的同时，不断探索各种机械和催化方案。

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