Importance of MM Polarization in QM/MM Studies of Enzymatic Reactions: Assessment of the QM/MM Drude Oscillator Model

For accurate quantum mechanics/molecular mechanics (QM/MM) studies of enzymatic reactions, it is desirable to include MM polarization, for example by using the Drude oscillator (DO) model. For a long time, such studies were hampered by the lack of well-tested polarizable force fields for proteins. Following up on a recent preliminary QM/MM-DO assessment (<i>J. Chem. Theory. Comput.</i> <b>2014</b>, <i>10</i>, 1795–1809), we now report a comprehensive investigation of the effects of MM polarization on two enzymatic reactions, namely the Claisen rearrangement in chorismate mutase and the hydroxylation reaction in p-hydroxybenzoate hydroxylase, using the QM/CHARMM-DO model and two QM methods (B3LYP, OM2). We compare the results from extensive geometry optimizations and free energy simulations at the QM/MM-DO level to those obtained from analogous calculations at the conventional QM/MM level

Hybrid Quantum Mechanics/Molecular Mechanics/Coarse Grained Modeling: A Triple-Resolution Approach for Biomolecular Systems

We present a hybrid quantum mechanics/molecular mechanics/coarse-grained (QM/MM/CG) multiresolution approach for solvated biomolecular systems. The chemically important active-site region is treated at the QM level. The biomolecular environment is described by an atomistic MM force field, and the solvent is modeled with the CG Martini force field using standard or polarizable (pol-CG) water. Interactions within the QM, MM, and CG regions, and between the QM and MM regions, are treated in the usual manner, whereas the CG–MM and CG–QM interactions are evaluated using the virtual sites approach. The accuracy and efficiency of our implementation is tested for two enzymes, chorismate mutase (CM) and <i>p</i>-hydroxybenzoate hydroxylase (PHBH). In CM, the QM/MM/CG potential energy scans along the reaction coordinate yield reaction energies that are too large, both for the standard and polarizable Martini CG water models, which can be attributed to adverse effects of using large CG water beads. The inclusion of an atomistic MM water layer (10 Å for uncharged CG water and 5 Å for polarizable CG water) around the QM region improves the energy profiles compared to the reference QM/MM calculations. In analogous QM/MM/CG calculations on PHBH, the use of the pol-CG description for the outer water does not affect the stabilization of the highly charged FADHOOH-pOHB transition state compared to the fully atomistic QM/MM calculations. Detailed performance analysis in a glycine–water model system indicates that computation times for QM energy and gradient evaluations at the density functional level are typically reduced by 40–70% for QM/MM/CG relative to fully atomistic QM/MM calculations

Optimized Lennard-Jones Parameters for Druglike Small Molecules

Meaningful efforts in computer-aided drug design (CADD) require accurate molecular mechanical force fields to quantitatively characterize protein–ligand interactions, ligand hydration free energies, and other ligand physical properties. Atomic models of new compounds are commonly generated by analogy from the predefined tabulated parameters of a given force field. Two widely used approaches following this strategy are the General Amber Force Field (GAFF) and the CHARMM General Force Field (CGenFF). An important limitation of using pretabulated parameter values is that they may be inadequate in the context of a specific molecule. To resolve this issue, we previously introduced the General Automated Atomic Model Parameterization (GAAMP) for automatically generating the parameters of atomic models of small molecules, using the results from ab initio quantum mechanical (QM) calculations as target data. The GAAMP protocol uses QM data to optimize the bond, valence angle, and dihedral angle internal parameters, and atomic partial charges. However, since the treatment of van der Waals interactions based on QM is challenging and may often be unreliable, the Lennard-Jones 6–12 parameters are kept unchanged from the initial atom types assignments (GAFF or CGenFF), which limits the accuracy that can be achieved by these models. To address this issue, a new set of Lennard-Jones 6–12 parameters was systematically optimized to reproduce experimental neat liquid densities and enthalpies of vaporization for a large set of 430 compounds, covering a wide range of chemical functionalities. Calculations of the hydration free energy indicate that optimal accuracy for these models is achieved when the molecule–water van der Waals dispersion is rescaled by a factor of 1.115. The final optimized model yields an average unsigned error of 0.79 kcal/mol in the hydration free energies

Optimized Lennard-Jones Parameters for Druglike Small Molecules

Meaningful efforts in computer-aided drug design (CADD) require accurate molecular mechanical force fields to quantitatively characterize protein–ligand interactions, ligand hydration free energies, and other ligand physical properties. Atomic models of new compounds are commonly generated by analogy from the predefined tabulated parameters of a given force field. Two widely used approaches following this strategy are the General Amber Force Field (GAFF) and the CHARMM General Force Field (CGenFF). An important limitation of using pretabulated parameter values is that they may be inadequate in the context of a specific molecule. To resolve this issue, we previously introduced the General Automated Atomic Model Parameterization (GAAMP) for automatically generating the parameters of atomic models of small molecules, using the results from ab initio quantum mechanical (QM) calculations as target data. The GAAMP protocol uses QM data to optimize the bond, valence angle, and dihedral angle internal parameters, and atomic partial charges. However, since the treatment of van der Waals interactions based on QM is challenging and may often be unreliable, the Lennard-Jones 6–12 parameters are kept unchanged from the initial atom types assignments (GAFF or CGenFF), which limits the accuracy that can be achieved by these models. To address this issue, a new set of Lennard-Jones 6–12 parameters was systematically optimized to reproduce experimental neat liquid densities and enthalpies of vaporization for a large set of 430 compounds, covering a wide range of chemical functionalities. Calculations of the hydration free energy indicate that optimal accuracy for these models is achieved when the molecule–water van der Waals dispersion is rescaled by a factor of 1.115. The final optimized model yields an average unsigned error of 0.79 kcal/mol in the hydration free energies

Optimized Lennard-Jones Parameters for Druglike Small Molecules

Meaningful efforts in computer-aided drug design (CADD) require accurate molecular mechanical force fields to quantitatively characterize protein–ligand interactions, ligand hydration free energies, and other ligand physical properties. Atomic models of new compounds are commonly generated by analogy from the predefined tabulated parameters of a given force field. Two widely used approaches following this strategy are the General Amber Force Field (GAFF) and the CHARMM General Force Field (CGenFF). An important limitation of using pretabulated parameter values is that they may be inadequate in the context of a specific molecule. To resolve this issue, we previously introduced the General Automated Atomic Model Parameterization (GAAMP) for automatically generating the parameters of atomic models of small molecules, using the results from ab initio quantum mechanical (QM) calculations as target data. The GAAMP protocol uses QM data to optimize the bond, valence angle, and dihedral angle internal parameters, and atomic partial charges. However, since the treatment of van der Waals interactions based on QM is challenging and may often be unreliable, the Lennard-Jones 6–12 parameters are kept unchanged from the initial atom types assignments (GAFF or CGenFF), which limits the accuracy that can be achieved by these models. To address this issue, a new set of Lennard-Jones 6–12 parameters was systematically optimized to reproduce experimental neat liquid densities and enthalpies of vaporization for a large set of 430 compounds, covering a wide range of chemical functionalities. Calculations of the hydration free energy indicate that optimal accuracy for these models is achieved when the molecule–water van der Waals dispersion is rescaled by a factor of 1.115. The final optimized model yields an average unsigned error of 0.79 kcal/mol in the hydration free energies

Optimized Lennard-Jones Parameters for Druglike Small Molecules

Meaningful efforts in computer-aided drug design (CADD) require accurate molecular mechanical force fields to quantitatively characterize protein–ligand interactions, ligand hydration free energies, and other ligand physical properties. Atomic models of new compounds are commonly generated by analogy from the predefined tabulated parameters of a given force field. Two widely used approaches following this strategy are the General Amber Force Field (GAFF) and the CHARMM General Force Field (CGenFF). An important limitation of using pretabulated parameter values is that they may be inadequate in the context of a specific molecule. To resolve this issue, we previously introduced the General Automated Atomic Model Parameterization (GAAMP) for automatically generating the parameters of atomic models of small molecules, using the results from ab initio quantum mechanical (QM) calculations as target data. The GAAMP protocol uses QM data to optimize the bond, valence angle, and dihedral angle internal parameters, and atomic partial charges. However, since the treatment of van der Waals interactions based on QM is challenging and may often be unreliable, the Lennard-Jones 6–12 parameters are kept unchanged from the initial atom types assignments (GAFF or CGenFF), which limits the accuracy that can be achieved by these models. To address this issue, a new set of Lennard-Jones 6–12 parameters was systematically optimized to reproduce experimental neat liquid densities and enthalpies of vaporization for a large set of 430 compounds, covering a wide range of chemical functionalities. Calculations of the hydration free energy indicate that optimal accuracy for these models is achieved when the molecule–water van der Waals dispersion is rescaled by a factor of 1.115. The final optimized model yields an average unsigned error of 0.79 kcal/mol in the hydration free energies