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      Assessment and acceleration of binding energy calculations for protein-ligand complexes by the fragment molecular orbital method

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      Journal of Computational Chemistry
      Wiley-Blackwell

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          Abstract

          In the field of drug discovery, it is important to accurately predict the binding affinities between target proteins and drug applicant molecules. Many of the computational methods available for evaluating binding affinities have adopted molecular mechanics-based force fields, although they cannot fully describe protein-ligand interactions. A noteworthy computational method in development involves large-scale electronic structure calculations. Fragment molecular orbital (FMO) method, which is one of such large-scale calculation techniques, is applied in this study for calculating the binding energies between proteins and ligands. By testing the effects of specific FMO calculation conditions (including fragmentation size, basis sets, electron correlation, exchange-correlation functionals, and solvation effects) on the binding energies of the FK506-binding protein and 10 ligand complex molecule, we have found that the standard FMO calculation condition, FMO2-MP2/6-31G(d), is suitable for evaluating the protein-ligand interactions. The correlation coefficient between the binding energies calculated with this FMO calculation condition and experimental values is determined to be R = 0.77. Based on these results, we also propose a practical scheme for predicting binding affinities by combining the FMO method with the quantitative structure-activity relationship (QSAR) model. The results of this combined method can be directly compared with experimental binding affinities. The FMO and QSAR combined scheme shows a higher correlation with experimental data (R = 0.91). Furthermore, we propose an acceleration scheme for the binding energy calculations using a multilayer FMO method focusing on the protein-ligand interaction distance. Our acceleration scheme, which uses FMO2-HF/STO-3G:MP2/6-31G(d) at R(int) = 7.0 Å, reduces computational costs, while maintaining accuracy in the evaluation of binding energy.

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          Improved second-order Møller–Plesset perturbation theory by separate scaling of parallel- and antiparallel-spin pair correlation energies

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            Statistical Mechanical Theory of Transport Processes. VII. The Coefficient of Thermal Conductivity of Monatomic Liquids

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              Assessment of the Performance of the M05-2X and M06-2X Exchange-Correlation Functionals for Noncovalent Interactions in Biomolecules.

              The highly parametrized, empirical exchange-correlation functionals, M05-2X and M06-2X, developed by Zhao and Truhlar have been shown to describe noncovalent interactions better than density functionals which are currently in common use. However, these methods have yet to be fully benchmarked for the types of interactions important in biomolecules. M05-2X and M06-2X are claimed to capture "medium-range" electron correlation; however, the "long-range" electron correlation neglected by these functionals can also be important in the binding of noncovalent complexes. Here we test M05-2X and M06-2X for the nucleic acid base pairs in the JSCH-2005 database. Using the CCSD(T) binding energies as a benchmark, the performance of these functionals is compared to that of a nonempirical density functional, PBE, and also to that of PBE plus Grimme's empirical dispersion correction, PBE-D. Due to the importance of "long-range" electron correlation in hydrogen-bonded and interstrand base pairs, PBE-D provides more accurate interaction energies on average for the JSCH-2005 database when compared to M05-2X or M06-2X. M06-2X does, however, perform somewhat better than PBE-D for interactions between stacked base pairs.
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                Author and article information

                Journal
                Journal of Computational Chemistry
                J. Comput. Chem.
                Wiley-Blackwell
                01928651
                November 15 2015
                November 15 2015
                : 36
                : 30
                : 2209-2218
                Article
                10.1002/jcc.24055
                26400829
                1be8c865-a441-4817-aae7-d868fe28d200
                © 2015

                http://doi.wiley.com/10.1002/tdm_license_1.1

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