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Accelerated Computation of Free Energy Profile at Ab Initio Quantum Mechanical/Molecular Mechanics Accuracy via a Semiempirical Reference Potential. 3. Gaussian Smoothing on Density-of-States.

ABSTRACT: Calculations of the free energy profile, also known as potential of mean force (PMF), along a chosen collective variable (CV) are now routinely applied in the studies of chemical processes, such as enzymatic reactions and chemical reactions in condensed phases. However, if the ab initio quantum mechanical/molecular mechanics (QM/MM) level of accuracy is required for the PMF, it can be formidably demanding even with the most advanced enhanced sampling methods, such as umbrella sampling. To ameliorate this difficulty, we developed a novel method for the computation of the free energy profile based on the reference-potential method recently, in which a low-level reference Hamiltonian is employed for phase space sampling and the free energy profile can be corrected to the level of interest (the target Hamiltonian) by energy reweighting in a nonparametric way. However, when the reference Hamiltonian is very different from the target Hamiltonian, the calculated ensemble averages, including the PMF, often suffer from numerical instability, which mainly comes from the overestimation of the density-of-states (DoS) in the low-energy region. Stochastic samplings of these low-energy configurations are rare events, and some low-energy conformations may get oversampled in simulations of a finite length. In this work, an assumption of Gaussian distribution is applied to the DoS in each CV bin, and the weight of each configuration is rescaled according to the accumulated DoS. The results show that this smoothing process can remarkably reduce the ruggedness of the PMF and increase the reliability of the reference-potential method.

SUBMITTER: Hu W

PROVIDER: S-EPMC7658029 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Accelerated Computation of Free Energy Profile at <i>Ab Initio</i> Quantum Mechanical/Molecular Mechanics Accuracy via a Semiempirical Reference Potential. 3. Gaussian Smoothing on Density-of-States.

Hu Wenxin W Li Pengfei P Wang Jia-Ning JN Xue Yuanfei Y Mo Yan Y Zheng Jun J Pan Xiaoliang X Shao Yihan Y Mei Ye Y

Journal of chemical theory and computation 20201006 11

Calculations of the free energy profile, also known as potential of mean force (PMF), along a chosen collective variable (CV) are now routinely applied in the studies of chemical processes, such as enzymatic reactions and chemical reactions in condensed phases. However, if the <i>ab initio</i> quantum mechanical/molecular mechanics (QM/MM) level of accuracy is required for the PMF, it can be formidably demanding even with the most advanced enhanced sampling methods, such as umbrella sampling. To ...[more]

PMID: 32975951

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Project description:Reliable studies of enzymatic reactions by combined quantum mechanics/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 very large computer time for the evaluation of the QM energy, which in turn makes it extremely challenging to perform proper configurational sampling. A seemingly reasonable alternative is to perform energy minimization studies of the type used in gas-phase ab initio studies. However, it is hard to see why such an approach should give reliable results in protein active sites. To examine the problems with energy minimization QM/MM approaches, we chose the hypothetical reaction of a metaphosphate ion with water in the Ras.GAP complex. This hypothetical reaction served as a simple benchmark reaction. The possible problems with the QM/MM minimization were explored by generating several protein configurations from long MD simulations and using energy minimization and scanning of the reaction coordinates to evaluate the corresponding potential energy surfaces of the reaction for each of these different protein configurations. Comparing these potential energy surfaces, we found major variations of the corresponding minima. Furthermore, the reaction energies and activation energies also varied significantly even for similar protein configurations. The specific coordination of a magnesium ion, present in the active center of the protein complex, turned out to influence the energetics of the reaction in a major way, where a direct coordination to the reactant leads to an increase of the activation energy by 17 kcal/mol. Apparently, using energy minimization to generate potential surfaces for an enzymatic reaction, while starting from a single protein structure, could lead to major errors in calculations of activation free energies and binding free energies. Thus we believe that extensive samplings of the configurational space of the protein are essential for meaningful determination of the energetics of enzymatic reactions. The possible relevance of our conclusion with regard to a recent study of the RasGAP reaction is discussed.

Dataset Information

Accelerated Computation of Free Energy Profile at Ab Initio Quantum Mechanical/Molecular Mechanics Accuracy via a Semiempirical Reference Potential. 3. Gaussian Smoothing on Density-of-States.

Publications

Accelerated Computation of Free Energy Profile at <i>Ab Initio</i> Quantum Mechanical/Molecular Mechanics Accuracy via a Semiempirical Reference Potential. 3. Gaussian Smoothing on Density-of-States.

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