Producing DFT/MM enzyme reaction trajectories from SCC‐DFTB/MM driving forces to probe the underlying electronics of a glycosyltransferase reaction

The SCC‐DFTB/MIO/CHARMM free energy surface for a glycosyltransferase, TcTS, is benchmarked against a DFT/MM reaction trajectory using the same CHARMM MM force field ported to the NWChem package. The popular B3LYP functional, against which the MIO parameter set was parameterized is used to optimize TS structures and run DFT reaction dynamics. A novel approach was used to generate reaction forces from a SCC‐DFTB/MIO/CHARMM reaction surface to drive B3LYP/6‐31G/MM and B3LYP/6‐31G(d)/MM reaction trajectories. Although TS structures compare favorably, differences stemming primarily from a minimal basis set approximation prevented a successful 6‐31G(d) FEARCF reaction dynamics trajectory. None the less, the dynamic evolution of the B3LYP/6‐31G/MM‐computed electron density provided an opportunity to perform NBO analysis along the reaction trajectory. Here, we illustrate that a successful ab initio reaction trajectory is computationally accessible when the underlying potential energy function of the semi‐empirical method used to produce driving forces is sufficiently close to the ab initio potential. © 2017 Wiley Periodicals, Inc.     

QM/MM study of the absorption spectra of DsRed.M1 chromophores

We report geometries and vertical excitation energies for the red and green chromophores of the DsRed.M1 protein in the gas phase and in the solvated protein environment. Geometries are optimized using density functional theory (DFT, B3LYP functional) for the isolated chromophores and combined quantum mechanical/molecular mechanical (QM/MM) methods for the protein (B3LYP/MM). Vertical excitation energies are computed using DFT/MRCI, OM2/MRCI, and TDDFT as QM methods. In the case of the red chromophore, there is a general blue shift in the excitation energies when going from the isolated chromophore to the protein, which is caused both by structural changes and by electrostatic interactions with the environment. For the lowest ππ* transition, these two factors contribute to a similar extent to the overall DFT/MRCI shift of 0.4 eV. An enlargement of the QM region to include active‐site residues does not change the DFT/MRCI excitation energies much. The DFT/MRCI results are closest to experiment for both chromophores. OM2/MRCI and TDDFT overestimate the first vertical excitation energy by 0.3–0.5 and 0.2–0.4 eV, respectively, relative to the experimental or DFT/MRCI values. The experimental gap of 0.35 eV between the lowest ππ* excitation energies of the red (cis‐acylimine) and green (trans‐peptide) forms is well reproduced by DFT/MRCI and TDDFT (0.32 and 0.37 eV, respectively). A histogram spectrum for an equal mixture of the two forms, generated by OM2/MRCI calculations on 450 snapshots along molecular dynamics trajectories, matches the experimental spectrum quite well, with a gap of 0.23 eV and an overall blue shift of about 0.3 eV. DFT/MRCI appears as an attractive choice for calculating excitation energies in fluorescent proteins, without the shortcomings of TDDFT and computationally more affordable than CASSCF‐based approaches. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Infrared spectroscopy of N-methylacetamide in water from high-level QM/MM calculations简

The infrared(IR) spectra of the N-methylacetamide molecule in water are calculated by using the MD simulation with high-level QM/MM corrections. The B3LYP and MP2 levels with 6-311++G** basis set are used for the QM region, respectively. Our results show all IR spectra at the B3LYP level are well consistent with the corresponding MP2 results. A dynamical charge fluctuation is observed for each atom along the simulation trajectories due to the electrostatic polarization(EP) effects from surrounding solvent environment. We find that the QM/MM corrected IR spectra satisfactorily reproduce the experimental vibrational features of amide I–III modes.     

Modeling emission features of salicylidene aniline molecular crystals: A QM/QM’ approach

A new computational protocol relying on the use of electrostatic embedding, derived from QM/QM’ ONIOM calculations, to simulate the effect of the crystalline environment on the emission spectra of molecular crystals is here applied to the β‐form of salicylidene aniline (SA). The first singlet excited states (S₁) of the SA cis‐keto and trans‐keto conformers, surrounded by a cluster of other molecules representing the crystalline structure, were optimized by using a QM/QM’ ONIOM approach with and without electronic embedding. The model system consisting of the central salicylidene aniline molecule was treated at the DFT level by using either the B3LYP, PBE0, or the CAM‐B3LYP functional, whereas the real system was treated at the HF level. The CAM‐B3LYP/HF level of theory provides emission energies in good agreement with experiment with differences of ?20/?32 nm ( cis‐keto form) and ?8/?14 nm ( trans‐keto form), respectively, whereas notably larger differences are obtained using global hybrids. Though such differences on the optical properties arise from the density functional choice, the contribution of the electronic embedding is rather independent of the functional used. This plays in favor of a more general applicability of the present protocol to other crystalline molecular systems. © 2016 Wiley Periodicals, Inc.     

Development of massive multilevel molecular dynamics simulation program,platypus (PLATform for dYnamic protein unified simulation), for the elucidation of protein functions

A massively parallel program for quantum mechanical‐molecular mechanical (QM/MM) molecular dynamics simulation, called Platypus (PLATform for dYnamic Protein Unified Simulation), was developed to elucidate protein functions. The speedup and the parallelization ratio of Platypus in the QM and QM/MM calculations were assessed for a bacteriochlorophyll dimer in the photosynthetic reaction center (DIMER) on the K computer, a massively parallel computer achieving 10 PetaFLOPs with 705,024 cores. Platypus exhibited the increase in speedup up to 20,000 core processors at the HF/cc‐pVDZ and B3LYP/cc‐pVDZ, and up to 10,000 core processors by the CASCI(16,16)/6‐31G** calculations. We also performed excited QM/MM‐MD simulations on the chromophore of Sirius (SIRIUS) in water. Sirius is a pH‐insensitive and photo‐stable ultramarine fluorescent protein. Platypus accelerated on‐the‐fly excited‐state QM/MM‐MD simulations for SIRIUS in water, using over 4000 core processors. In addition, it also succeeded in 50‐ps (200,000‐step) on‐the‐fly excited‐state QM/MM‐MD simulations for the SIRIUS in water. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.     

Spectral tuning in visual pigments: an ONIOM(QM:MM) study on bovine rhodopsin and its mutants

We have investigated geometries and excitation energies of bovine rhodopsin and some of its mutants by hybrid quantum mechanical/molecular mechanical (QM/MM) calculations in ONIOM scheme, employing B3LYP and BLYP density functionals as well as DFTB method for the QM part and AMBER force field for the MM part. QM/MM geometries of the protonated Schiff-base 11- cis-retinal with B3LYP and DFTB are very similar to each other. TD-B3LYP/MM excitation energy calculations reproduce the experimental absorption maximum of 500 nm in the presence of native rhodopsin environment and predict spectral shifts due to mutations within 10 nm, whereas TD-BLYP/MM excitation energies have red-shift error of at least 50 nm. In the wild-type rhodopsin, Glu113 shifts the first excitation energy to blue and accounts for most of the shift found. Other amino acids individually contribute to the first excitation energy but their net effect is small. The electronic polarization effect is essential for reproducing experimental bond length alternation along the polyene chain in protonated Schiff-base retinal, which correlates with the computed first excitation energy. It also corrects the excitation energies and spectral shifts in mutants, more effectively for deprotonated Schiff-base retinal than for the protonated form. The protonation state and conformation of mutated residues affect electronic spectrum significantly. The present QM/MM calculations estimate not only the experimental excitation energies but also the source of spectral shifts in mutants.     

Modeling of phytochrome absorption spectra

Phytochromes constitute one of the six well‐characterized families of photosensory proteins in Nature. From the viewpoint of computational modeling, however, phytochromes have been the subject of much fewer studies than most other families of photosensory proteins, which is likely a consequence of relevant high‐resolution structural data becoming available only in recent years. In this work, hybrid quantum mechanics/molecular mechanics (QM/MM) methods are used to calculate UV‐vis absorption spectra of Deinococcus radiodurans bacteriophytochrome. We investigate how the choice of QM/MM methodology affects the resulting spectra and demonstrate that QM/MM methods can reproduce the experimental absorption maxima of both the Q and Soret bands with an accuracy of about 0.15 eV. Furthermore, we assess how the protein environment influences the intrinsic absorption of the bilin chromophore, with particular focus on the Q band underlying the primary photochemistry of phytochromes. © 2013 Wiley Periodicals, Inc.     

Rapid QM/MM approach for biomolecular systems under periodic boundary conditions: Combination of the density‐functional tight‐binding theory and particle mesh Ewald method

A quantum mechanical/molecular mechanical (QM/MM) approach based on the density‐functional tight‐binding (DFTB) theory is a useful tool for analyzing chemical reaction systems in detail. In this study, an efficient QM/MM method is developed by the combination of the DFTB/MM and particle mesh Ewald (PME) methods. Because the Fock matrix, which is required in the DFTB calculation, is analytically obtained by the PME method, the Coulomb energy is accurately and rapidly computed. For assessing the performance of this method, DFTB/MM calculations and molecular dynamics simulation are conducted for a system consisting of two amyloid‐β(1‐16) peptides and a zinc ion in explicit water under periodic boundary conditions. As compared with that of the conventional Ewald summation method, the computational cost of the Coulomb energy by utilizing the present approach is drastically reduced, i.e., 166.5 times faster. Furthermore, the deviation of the electronic energy is less than . © 2016 Wiley Periodicals, Inc.     

Less is more when simulating unsulfated glycosaminoglycan 3D‐structure: Comparison of GLYCAM06/TIP3P,PM3‐CARB1/TIP3P,and SCC‐DFTB‐D/TIP3P predictions with experiment

The 3D‐structure of extracellular matrix glycosaminoglycans is central to function, but is currently poorly understood. Resolving this will provide insight into their heterogeneous biological roles and help to realize their significant therapeutic potential. Glycosaminoglycan chemical isoforms are too numerous to study experimentally and simulation provides a tractable alternative. However, best practice for accurate calculation of glycosaminoglycan 3D‐structure within biologically relevant nanosecond timescales is uncertain. Here, we evaluate the ability of three potentials to reproduce experimentally observed glycosaminoglycan monosaccharide puckering, disaccharide 3D‐conformation, and characteristic solvent interactions. Temporal dynamics of unsulfated chondroitin, chondroitin‐4‐sulfate, and hyaluronan β(1→3) disaccharides were simulated within TIP3P explicit solvent unrestrained for 20 ns using the GLYCAM06 force‐field and two semi‐empirical quantum mechanics methods, PM3‐CARB1 and SCC‐DFTB‐D (both within a hybrid QM/MM formalism). Comparison of calculated and experimental properties (vicinal couplings, nuclear Overhauser enhancements, and glycosidic linkage geometries) showed that the carbohydrate‐specific parameterization of PM3‐CARB1 imparted quantifiable benefits on monosaccharide puckering and that the SCC‐DFTB‐D method (including an empirical correction for dispersion) best modeled the effects of hexosamine 4‐sulfation. However, paradoxically, the most approximate approach (GLYCAM06/TIP3P) was the best at predicting monosaccharide puckering, 3D‐conformation, and solvent interactions. Our data contribute to the debate and emerging consensus on the relative performance of these levels of theory for biological molecules. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Solvents effects on the mechanism of cellulose hydrolysis: A QM/MM study

This article reports a combined quantum mechanics/molecular mechanics (QM/MM) investigation on the acid hydrolysis of cellulose in water using two different models, cellobiose and a 40‐unit cellulose chain. The explicitly treated solvent molecules strongly influence the conformations, intramolecular hydrogen bonds, and exoanomeric effects in these models. As these features are largely responsible for the barrier to cellulose hydrolysis, the present QM/MM results for the pathways and reaction intermediates in water are expected to be more realistic than those from a former density functional theory (DFT) study with implicit solvent (CPCM). However, in a qualitative sense, there is reasonable agreement between the DFT/CPCM and QM/MM predictions for the reaction mechanism. Differences arise mainly from specific solute–solvent hydrogen bonds that are only captured by QM/MM and not by DFT/CPCM. © 2015 Wiley Periodicals, Inc.     

Water solvent effects using continuum and discrete models: The nitromethane molecule,CH3NO2

The first three valence transitions of the two nitromethane conformers (CH₃NO₂) are two dark n → π* transitions and a very intense π → π* transition. In this work, these transitions in gas‐phase and solvated in water of both conformers were investigated theoretically. The polarizable continuum model (PCM), two conductor‐like screening (COSMO) models, and the discrete sequential quantum mechanics/molecular mechanics (S‐QM/MM) method were used to describe the solvation effect on the electronic spectra. Time dependent density functional theory (TDDFT), configuration interaction including all single substitutions and perturbed double excitations (CIS(D)), the symmetry‐adapted‐cluster CI (SAC‐CI), the multistate complete active space second order perturbation theory (CASPT2), and the algebraic‐diagrammatic construction (ADC(2)) electronic structure methods were used. Gas‐phase CASPT2, SAC‐CI, and ADC(2) results are in very good agreement with published experimental and theoretical spectra. Among the continuum models, PCM combined either with CASPT2, SAC‐CI, or B3LYP provided good agreement with available experimental data. COSMO combined with ADC(2) described the overall trends of the transition energy shifts. The effect of increasing the number of explicit water molecules in the S‐QM/MM approach was discussed and the formation of hydrogen bonds was clearly established. By including explicitly 24 water molecules corresponding to the complete first solvation shell in the S‐QM/MM approach, the ADC(2) method gives more accurate results as compared to the TDDFT approach and with similar computational demands. The ADC(2) with S‐QM/MM model is, therefore, the best compromise for accurate solvent calculations in a polar environment. © 2015 Wiley Periodicals, Inc.     

QuanPol: A full spectrum and seamless QM/MM program

The quantum chemistry polarizable force field program (QuanPol) is implemented to perform combined quantum mechanical and molecular mechanical (QM/MM) calculations with induced dipole polarizable force fields and induced surface charge continuum solvation models. The QM methods include Hartree–Fock method, density functional theory method (DFT), generalized valence bond theory method, multiconfiguration self‐consistent field method, Møller–Plesset perturbation theory method, and time‐dependent DFT method. The induced dipoles of the MM atoms and the induced surface charges of the continuum solvation model are self‐consistently and variationally determined together with the QM wavefunction. The MM force field methods can be user specified, or a standard force field such as MMFF94, Chemistry at Harvard Molecular Mechanics (CHARMM), Assisted Model Building with Energy Refinement (AMBER), and Optimized Potentials for Liquid Simulations‐All Atom (OPLS‐AA). Analytic gradients for all of these methods are implemented so geometry optimization and molecular dynamics (MD) simulation can be performed. MD free energy perturbation and umbrella sampling methods are also implemented. © 2013 Wiley Periodicals, Inc.     

Developing ab initio quality force fields from condensed phase quantum-mechanics/molecular-mechanics calculations through the adaptive force matching method

A new method called adaptive force matching (AFM) has been developed that is capable of producing high quality force fields for condensed phase simulations. This procedure involves the parametrization of force fields to reproduce ab initio forces obtained from condensed phase quantum-mechanics/molecular-mechanics (QM/MM) calculations. During the procedure, the MM part of the QM/MM is iteratively improved so as to approach ab initio quality. In this work, the AFM method has been tested to parametrize force fields for liquid water so that the resulting force fields reproduce forces calculated using the ab initio MP2 and the Kohn-Sham density functional theory with the Becke-Lee-Yang-Parr (BLYP) and Becke three-parameter LYP (B3LYP) exchange correlation functionals. The AFM force fields generated in this work are very simple to evaluate and are supported by most molecular dynamics (MD) codes. At the same time, the quality of the forces predicted by the AFM force fields rivals that of very expensive ab initio calculations and are found to successfully reproduce many experimental properties. The site-site radial distribution functions (RDFs) obtained from MD simulations using the force field generated from the BLYP functional through AFM compare favorably with the previously published RDFs from Car-Parrinello MD simulations with the same functional. Technical aspects of AFM such as the optimal QM cluster size, optimal basis set, and optimal QM method to be used with the AFM procedure are discussed in this paper.     

Methodological aspects of QM/MM calculations: A case study on matrix metalloproteinase‐2

We address methodological issues in quantum mechanics/molecular mechanics (QM/MM) calculations on a zinc‐dependent enzyme. We focus on the first stage of peptide bond cleavage by matrix metalloproteinase‐2 (MMP‐2), that is, the nucleophilic attack of the zinc‐coordinating water molecule on the carbonyl carbon atom of the scissile fragment of the substrate. This step is accompanied by significant charge redistribution around the zinc cation, bond cleavage, and bond formation. We vary the size and initial geometry of the model system as well as the computational protocol to demonstrate the influence of these choices on the results obtained. We present QM/MM potential energy profiles for a set of snapshots randomly selected from QM/MM‐based molecular dynamics simulations and analyze the differences in the computed profiles in structural terms. Since the substrate in MMP‐2 is located on the protein surface, we investigate the influence of the thickness of the water layer around the enzyme on the QM/MM energy profile. Thin water layers (0–2 Å) give unrealistic results because of structural reorganizations in the active‐site region at the protein surface. A 12 Å water layer appears to be sufficient to capture the effect of the solvent; the corresponding QM/MM energy profile is very close to that obtained from QM/MM/SMBP calculations using the solvent macromolecular boundary potential (SMBP). We apply the optimized computational protocol to explain the origin of the different catalytic activity of the Glu116Asp mutant: the energy barrier for the first step is higher, which is rationalized on structural grounds. © 2016 Wiley Periodicals, Inc.     

IR spectra of N-methylacetamide in water predicted by combined quantum mechanical/molecular mechanical molecular dynamics simulations

We applied the combined quantum mechanical (QM)/molecular mechanical (MM) molecular dynamics (MD) simulation method in assessing IR spectra of N-methylacetamide and its deuterated form in aqueous solutions. The model peptide is treated at the Austin Model 1 (AM1) level and the induced dipole effects by the solvent are incorporated in fluctuating solute dipole moments, which are calculated using partial charges from Mulliken population analyses without resorting to any available high-level ab initio dipole moment data. Fourier transform of the solute dipole autocorrelation function produces in silico IR spectra, in which the relative peak intensities and bandwidths of major amide bands are quantitatively compatible with experimental results only when both geometric and electronic polarizations of the peptide by the solvent are dealt with at the same quantum-mechanical level. We cast light on the importance of addressing dynamic charge fluctuations of the solute in calculating IR spectra by comparing classical and QM/MM MD simulation results. We propose the adjustable scaling factors for each amide mode to be directly compared with experimental data.     

New QM/MM implementation of the DFTB3 method in the gromacs package

The approximate density‐functional tight‐binding theory method DFTB3 has been implemented in the quantum mechanics/molecular mechanics (QM/MM) framework of the Gromacs molecular simulation package. We show that the efficient smooth particle–mesh Ewald implementation of Gromacs extends to the calculation of QM/MM electrostatic interactions. Further, we make use of the various free‐energy functionalities provided by Gromacs and the PLUMED plugin. We exploit the versatility and performance of the current framework in three typical applications of QM/MM methods to solve biophysical problems: (i) ultrafast proton transfer in malonaldehyde, (ii) conformation of the alanine dipeptide, and (iii) electron‐induced repair of a DNA lesion. Also discussed is the further development of the framework, regarding mostly the options for parallelization. © 2015 Wiley Periodicals, Inc.     

The implementation of a fast and accurate QM/MM potential method in Amber

Version 9 of the Amber simulation programs includes a new semi-empirical hybrid QM/MM functionality. This includes support for implicit solvent (generalized Born) and for periodic explicit solvent simulations using a newly developed QM/MM implementation of the particle mesh Ewald (PME) method. The code provides sufficiently accurate gradients to run constant energy QM/MM MD simulations for many nanoseconds. The link atom approach used for treating the QM/MM boundary shows improved performance, and the user interface has been rewritten to bring the format into line with classical MD simulations. Support is provided for the PM3, PDDG/PM3, PM3CARB1, AM1, MNDO, and PDDG/MNDO semi-empirical Hamiltonians as well as the self-consistent charge density functional tight binding (SCC-DFTB) method. Performance has been improved to the point where using QM/MM, for a QM system of 71 atoms within an explicitly solvated protein using periodic boundaries and PME requires less than twice the cpu time of the corresponding classical simulation.     

Nitrile and thiocyanate IR probes: molecular dynamics simulation studies

Nitrile- and thiocyanate-derivatized amino acids have been found to be useful IR probes for investigating their local electrostatic environments in proteins. To shed light on the CN stretch frequency shift and spectral lineshape change induced by interactions with hydrogen-bonding solvent molecules, we carried out both classical and quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations for MeCN and MeSCN in water. These QM/MM and conventional force field MD simulation results were found to be inconsistent with the experimental results as well as with the high-level ab initio calculation results of MeCN-water and MeSCN-water potential energies. Thus, a new set of atomic partial charges of MeCN and MeSCN is obtained. By using the MD simulation trajectories and the electrostatic potential model recently developed, the CN and SCN stretching mode frequency trajectories were obtained and used to simulate the IR spectra. The C[Triple Bond]N frequency blueshifts of MeCN and MeSCN in water are estimated to be 9.0 and 1.9 cm(-1), respectively, in comparison with those of gas phase values. These values are found to be in reasonable agreement with the experimentally measured IR spectra of MeCN, MeSCN, beta-cyano-L-alanine, and cyanylated cysteine in water and other polar solvents.     

A valence bond model for aqueous Cu(II) and Zn(II) ions in the AMOEBA polarizable force field

A general molecular mechanics (MM) model for treating aqueous Cu²⁺ and Zn²⁺ ions was developed based on valence bond (VB) theory and incorporated into the atomic multipole optimized energetics for biomolecular applications (AMOEBA) polarizable force field. Parameters were obtained by fitting MM energies to that computed by ab initio methods for gas‐phase tetra‐ and hexa‐aqua metal complexes. Molecular dynamics (MD) simulations using the proposed AMOEBA‐VB model were performed for each transition metal ion in aqueous solution, and solvent coordination was evaluated. Results show that the AMOEBA‐VB model generates the correct square‐planar geometry for gas‐phase tetra‐aqua Cu²⁺ complex and improves the accuracy of MM model energetics for a number of ligation geometries when compared to quantum mechanical (QM) computations. On the other hand, both AMOEBA and AMOEBA‐VB generate results for Zn²⁺–water complexes in good agreement with QM calculations. Analyses of the MD trajectories revealed a six‐coordination first solvation shell for both Cu²⁺ and Zn²⁺ ions in aqueous solution, with ligation geometries falling in the range reported by previous studies. © 2012 Wiley Periodicals, Inc.