Absolute Free Energy of Binding Calculations for Macrophage Migration Inhibitory Factor in Complex with a Druglike Inhibitor.

Calculation of the absolute free energy of binding (ΔGbind) for a complex in solution is challenging owing to the need for adequate configurational sampling and an accurate energetic description, typically with a force field (FF). In this study, Monte Carlo (MC) simulations with improved side-chain and backbone sampling are used to assess ΔGbind for the complex of a druglike inhibitor (MIF180) with the protein macrophage migration inhibitory factor (MIF) using free energy perturbation (FEP) calculations. For comparison, molecular dynamics (MD) simulations were employed as an alternative sampling method for the same system. With the OPLS-AA/M FF and CM5 atomic charges for the inhibitor, the ΔGbind results from the MC/FEP and MD/FEP simulations, -8.80 ± 0.74 and -8.46 ± 0.85 kcal/mol, agree well with each other and with the experimental value of -8.98 ± 0.28 kcal/mol. The convergence of the results and analysis of the trajectories indicate that sufficient sampling was achieved for both approaches. Repeating the MD/FEP calculations using current versions of the CHARMM and AMBER FFs led to a 6 kcal/mol range of computed ΔGbind. These results show that calculation of accurate ΔGbind for large ligands is both feasible and numerically equivalent, within error limits, using either methodology.

Enhanced Monte Carlo Methods for Modeling Proteins Including Computation of Absolute Free Energies of Binding.

The generation of a complete ensemble of geometrical configurations is required to obtain reliable estimations of absolute binding free energies by alchemical free energy methods. Molecular dynamics (MD) is the most popular sampling method, but the representation of large biomolecular systems may be incomplete owing to energetic barriers that impede efficient sampling of the configurational space. Monte Carlo (MC) methods can possibly overcome this issue by adapting the attempted movement sizes to facilitate transitions between alternative local-energy minima. In this study, we present an MC statistical mechanics algorithm to explore the protein-ligand conformational space with emphasis on the motions of the protein backbone and side chains. The parameters for each MC move type were optimized to better reproduce conformational distributions of 18 dipeptides and the well-studied T4-lysozyme L99A protein. Next, the performance of the improved MC algorithms was evaluated by computing absolute free energies of binding for L99A lysozyme with benzene and seven analogs. Results for benzene with L99A lysozyme from MD and the optimized MC protocol were found to agree within 0.6 kcal/mol, while a mean unsigned error of 1.2 kcal/mol between MC results and experiment was obtained for the seven benzene analogs. Significant advantages in computation speed are also reported with MC over MD for similar extents of configurational sampling.

Application of a BOSS-Gaussian interface for QM/MM simulations of Henry and methyl transfer reactions.

Hybrid quantum mechanics and molecular mechanics (QM/MM) computer simulations have become an indispensable tool for studying chemical and biological phenomena for systems too large to treat with QM alone. For several decades, semiempirical QM methods have been used in QM/MM simulations. However, with increased computational resources, the introduction of ab initio and density function methods into on-the-fly QM/MM simulations is being increasingly preferred. This adaptation can be accomplished with a program interface that tethers independent QM and MM software packages. This report introduces such an interface for the BOSS and Gaussian programs, featuring modification of BOSS to request QM energies and partial atomic charges from Gaussian. A customizable C-shell linker script facilitates the interprogram communication. The BOSS-Gaussian interface also provides convenient access to Charge Model 5 (CM5) partial atomic charges for multiple purposes including QM/MM studies of reactions. In this report, the BOSS-Gaussian interface is applied to a nitroaldol (Henry) reaction and two methyl transfer reactions in aqueous solution. Improved agreement with experiment is found by determining free-energy surfaces with MP2/CM5 QM/MM simulations than previously reported investigations using semiempirical methods.

Determination of partial molar volumes from free energy perturbation theory.

Partial molar volume is an important thermodynamic property that gives insights into molecular size and intermolecular interactions in solution. Theoretical frameworks for determining the partial molar volume (V°) of a solvated molecule generally apply Scaled Particle Theory or Kirkwood-Buff theory. With the current abilities to perform long molecular dynamics and Monte Carlo simulations, more direct methods are gaining popularity, such as computing V° directly as the difference in computed volume from two simulations, one with a solute present and another without. Thermodynamically, V° can also be determined as the pressure derivative of the free energy of solvation in the limit of infinite dilution. Both approaches are considered herein with the use of free energy perturbation (FEP) calculations to compute the necessary free energies of solvation at elevated pressures. Absolute and relative partial molar volumes are computed for benzene and benzene derivatives using the OPLS-AA force field. The mean unsigned error for all molecules is 2.8 cm(3) mol(-1). The present methodology should find use in many contexts such as the development and testing of force fields for use in computer simulations of organic and biomolecular systems, as a complement to related experimental studies, and to develop a deeper understanding of solute-solvent interactions.