The ability of atomic interaction parameters generated using the Automated Topology Builder and Repository version 3.0 (ATB3.0) to predict experimental hydration free enthalpies (ΔG water) and ...solvation free enthalpies in the apolar solvent hexane (ΔG hexane) is presented. For a validation set of 685 molecules the average unsigned error (AUE) between ΔG water values calculated using the ATB3.0 and experiment is 3.8 kJ·mol–1. The slope of the line of best fit is 1.00, the intercept −1.0 kJ·mol–1, and the R 2 0.90. For the more restricted set of 239 molecules used to validate OPLS3 ( J. Chem. Theory Comput. 2016, 12, 281−296, DOI: 10.1021/acs.jctc.5b00864 ) the AUE using the ATB3.0 is just 2.7 kJ·mol–1 and the R 2 0.93. A roadmap for further improvement of the ATB parameters is presented together with a discussion of the challenges of validating force fields against the available experimental data.
•Induced polarisation is an essential component of biomolecular interactions like cation-pi, hydrogen bonding, and ionic interactions.•Advances in simulation algorithms and computing hardware have ...made the rigorous inclusion of these interactions into new models.•Recent simulations have examined the effects of induced polarization on membrane permeation, ion-biomolecule interactions, and protein dynamics.
The quality of biomolecular simulations critically depends on the accuracy of the force field used to calculate the potential energy of the molecular configurations. Currently, most simulations employ non-polarisable force fields, which describe electrostatic interactions as the sum of Coulombic interactions between fixed atomic charges. Polarisation of these charge distributions is incorporated only in a mean-field manner. In the past decade, extensive efforts have been devoted to developing simple, efficient, and yet generally applicable polarisable force fields for biomolecular simulations. In this review, we summarise the latest developments in accounting for key biomolecular interactions with polarisable force fields and applications to address challenging biological questions. In the end, we provide an outlook for future development in polarisable force fields.
In this work we propose a strategy based on quantum mechanical (QM) calculations to parametrize a polarizable force field for use in molecular dynamics (MD) simulations. We investigate the use of ...multiple atoms-in-molecules (AIM) strategies to partition QM determined molecular electron densities into atomic subregions. The partitioned atomic densities are subsequently used to compute atomic dispersion coefficients from effective exchange-hole-dipole moment (XDM) calculations. In order to derive values for the repulsive van der Waals parameters from first principles, we use a simple volume relation to scale effective atomic radii. Explicit inclusion of higher order dispersion coefficients was tested for a series of alkanes, and we show that combining C 6 and C 8 attractive terms together with a C 11 repulsive potential yields satisfying models when used in combination with our van der Waals parameters and electrostatic and bonded parameters as directly obtained from quantum calculations as well. This result highlights that explicit inclusion of higher order dispersion terms could be viable in simulation, and it suggests that currently available QM analysis methods allow for first-principles parametrization of molecular mechanics models.
Force field parametrization involves a complex set of linked optimization problems, with the goal of describing complex molecular interactions by using simple classical potential-energy functions ...that model Coulomb interactions, dispersion, and exchange repulsion. These functions comprise a set of atomic (and molecular) parameters and together with the bonded terms they constitute the molecular mechanics force field. Traditionally, many of these parameters have been fitted in a calibration approach in which experimental measures for thermodynamic and other relevant properties of small-molecule compounds are used for fitting and validation. As these approaches are laborious and time-consuming and represent an underdetermined optimization problem, we study methods to fit and derive an increasing number of parameters directly from electronic structure calculations, in order to greatly reduce possible parameter space for the remaining free parameters. In the current work we investigate a polarizable model with a higher order dispersion term for use in biomolecular simulation. Results for 49 biochemically relevant molecules are presented including updated parameters for hydrocarbon side chains. We show that our recently presented set of QM/MM derived atomic polarizabilities can be used in direct conjunction with partial charges and a higher order dispersion model that are quantum-mechanically determined, to freeze nearly all (i.e., 132 out of 138) nonbonded parameters to their quantum determined values.
Binding free energy (ΔG bind ) computation can play an important role in prioritizing compounds to be evaluated experimentally on their affinity for target proteins, yet fast and accurate ΔG bind ...calculation remains an elusive task. In this study, we compare the performance of two popular end-point methods, i.e., linear interaction energy (LIE) and molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA), with respect to their ability to correlate calculated binding affinities of 27 thieno3,2-dpyrimidine-6-carboxamide-derived sirtuin 1 (SIRT1) inhibitors with experimental data. Compared with the standard single-trajectory setup of MM/PBSA, our study elucidates that LIE allows to obtain direct (“absolute”) values for SIRT1 binding free energies with lower compute requirements, while the accuracy in calculating relative values for ΔG bind is comparable (Pearson’s r = 0.72 and 0.64 for LIE and MM/PBSA, respectively). We also investigate the potential of combining multiple docking poses in iterative LIE models and find that Boltzmann-like weighting of outcomes of simulations starting from different poses can retrieve appropriate binding orientations. In addition, we find that in this particular case study the LIE and MM/PBSA models can be optimized by neglecting the contributions from electrostatic and polar interactions to the ΔG bind calculations.
In this work, we propose an improved QM/MM-based strategy to determine condensed-phase polarizabilities and we use this approach to optimize a new and simple polarizable four-site water model for ...classical molecular simulation. For the determination of the model value for the polarizability from QM/MM, we show that our proposed consensus-fitting strategy significantly reduces the uncertainty in calculated polarizabilities in cases where the size of the local external electric field is small. By fitting electrostatic, polarization and dispersion properties of our water model based on quantum and/or combined QM/MM calculations, only a single model parameter (describing exchange repulsion) is left for empirical calibration. The resulting model performs well in describing relevant pure-liquid thermodynamic and transport properties, which illustrates the merit of our approach to minimize the number of free variables in our model.
The absence of an adequate reversal strategy to prevent and stop potential life-threatening bleeding complications is a major drawback to the clinical use of the direct oral inhibitors of blood ...coagulation factor Xa. Here we show that specific modifications of the substrate-binding aromatic S4 subpocket within the factor Xa active site disrupt high-affinity engagement of the direct factor Xa inhibitors. These modifications either entail amino-acid substitution of S4 subsite residues Tyr99 and/or Phe174 (chymotrypsinogen numbering), or extension of the 99-loop that borders the S4 subsite. The latter modifications led to the engineering of a factor Xa variant that is able to support coagulation in human plasma spiked with (supra-)physiological concentrations of direct factor Xa inhibitors. As such, this factor Xa variant has the potential to be employed to bypass the direct factor Xa inhibitor-mediated anticoagulation in patients that require restoration of blood coagulation.A major drawback in the clinical use of the oral anticoagulants that directly inhibit factor Xa in order to prevent blood clot formation is the potential for life threatening bleeding events. Here the authors describe factor Xa variants that are refractory to inhibition by these anticoagulants and could serve as rescue agents in treated patients.
The bacterial Cytochrome P450 (CYP) BM3 (CYP102A1) is one of the most active CYP isoforms. BM3 mutants can serve as a model for human drug-metabolizing CYPs and/or as biocatalyst for selective ...formation of drug metabolites. Hence, molecular and computational biologists have in the last two decades shown strong interest in the discovery and design of novel BM3 variants with optimized activity and selectivity for substrate conversion. This led e.g. to the discovery of mutant M11 that is able to metabolize a variety of drugs and drug-like compounds with relatively high activity. In order to further improve our understanding of CYP binding and reactions, we performed a co-crystallization study of mutant M11 and report here the three-dimensional structure M11 in complex with dithiothreitol (DTT) at a resolution of 2.16 Å. The structure shows that DTT can coordinate to the Fe atom in the heme group. UV/Vis spectroscopy and molecular dynamics simulation studies underline this finding and as first structure of the CYP BM3 mutant M11 in complex with a ligand, it offers a basis for structure-based design of novel mutants.
Calculating free energies of binding (ΔG bind) between ligands and their target protein is of major interest to drug discovery and safety, yet it is still associated with several challenges and ...difficulties. Linear interaction energy (LIE) is an efficient in silico method for ΔG bind computation. LIE models can be trained and used to directly calculate binding affinities from interaction energies involving ligands in the bound and unbound states only, and LIE can be combined with statistical weighting to calculate ΔG bind for flexible proteins that may bind their ligands in multiple orientations. Here, we investigate if LIE predictions can be effectively improved by explicitly including the entropy of (de)solvation into our free-energy calculations. For that purpose, we combine LIE calculations for the protein–ligand-bound state with explicit free-energy perturbation to rigorously compute the unbound ligand’s solvation free energy. We show that for 28 Cytochrome P450 2A6 (CYP2A6) ligands, coupling LIE with alchemical solvation free-energy calculation helps to improve obtained correlation between computed and reference (experimental) binding data.
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