Alchemical free energy calculations via metadynamics: Application to the theophylline-RNA aptamer complex.

We propose a computational workflow for robust and accurate prediction of both binding poses and their affinities at early stage in designing drug candidates. Small, rigid ligands with few intramolecular degrees of freedom, for example, fragment-like molecules, have multiple binding poses, even at a single binding site, and their affinities are often close to each other. We explore various structures of ligand binding to a target through metadynamics using a small number of collective variables, followed by reweighting to obtain the atomic coordinates. After identifying each binding pose by cluster analysis, we perform alchemical free energy calculations on each structure to obtain the overall value. We applied this protocol in computing free energy of binding for the theophylline-RNA aptamer complex. Of the six (meta)stable structures found, the most favorable binding structure is consistent with the structure obtained by NMR. The overall free energy of binding reproduces the experimental values very well.

Docking study and binding free energy calculation of poly (ADP-ribose) polymerase inhibitors.

Recently, the massively parallel computation of absolute binding free energy with a well-equilibrated system (MP-CAFEE) has been developed. The present study aimed to determine whether the MP-CAFEE method is useful for drug discovery research. In the drug discovery process, it is important for computational chemists to predict the binding affinity accurately without detailed structural information for protein/ligand complex. We investigated the absolute binding free energies for Poly (ADP-ribose) polymerase-1 (PARP-1)/inhibitor complexes, using the MP-CAFEE method. Although each docking model was used as an input structure, it was found that the absolute binding free energies calculated by MP-CAFEE are well consistent with the experimental ones. The accuracy of this method is much higher than that using molecular mechanics Poisson-Boltzmann/surface area (MM/PBSA). Although the simulation time is quite extensive, the reliable predictor of binding free energies would be a useful tool for drug discovery projects.

Massively parallel computation of absolute binding free energy with well-equilibrated states.

A force field formulator for organic molecules (FF-FOM) was developed to assign bond, angle, and dihedral parameters to arbitrary organic molecules in a unified manner including proteins and nucleic acids. With the unified force field parametrization we performed massively parallel computations of absolute binding free energies for pharmaceutical target proteins and ligands. Compared with the previous calculation with the ff99 force field in the Amber simulation package (Amber99) and the ligand charges produced by the Austin Model 1 bond charge correction (AM1-BCC), the unified parametrization gave better absolute binding energies for the FK506 binding protein (FKBP) and ligand system. Our method is based on extensive work measurement between thermodynamic states to calculate the free energy difference and it is also the same as the traditional free energy perturbation. There are important requirements for accurate calculations. The first is a well-equilibrated bound structure including the conformational change of the protein induced by the binding of the ligand. The second requirement is the convergence of the work distribution with a sufficient number of trajectories and dense spacing of the coupling constant between the ligand and the rest of the system. Finally, the most important requirement is the force field parametrization.

High-Level ab Initio Calculations To Improve Protein Backbone Dihedral Parameters.

We present new molecular mechanical dihedral parameters for the Ramachandran angles ϕ and ψ of a protein backbone based on high-level ab initio molecular orbital calculations for hydrogen-blocked or methyl-blocked glycine and alanine dipeptides. Fully relaxed 15° (ϕ, ψ) contour maps were calculated at the MP2/6-31G(d) level of theory. Finding out the lowest energy path for ϕ (or ψ) to change from -180° to 180° in the contour map, we performed a DF-LCCSD(T0)/Aug-cc-pVTZ//DF-LMP2/Aug-cc-pVTZ level calculation to get the torsional energy profiles of ϕ (or ψ). Molecular mechanical torsion profiles with AMBER force field variants significantly differed from the ab initio profiles, so we derived new molecular mechanical dihedral parameters of a protein backbone to fit the ab initio profiles.

Direct calculation of the binding free energies of FKBP ligands.

Direct calculations of the absolute free energies of binding for eight ligands to FKBP protein were performed using the Fujitsu BioServer massively parallel computer. Using the latest version of the general assisted model building with energy refinement (AMBER) force field for ligand model parameters and the Bennett acceptance ratio for computing free-energy differences, we obtained an excellent linear fit between the calculated and experimental binding free energies. The rms error from a linear fit is 0.4 kcal/mol for eight ligand complexes. In comparison with a previous study of the binding energies of these same eight ligand complexes, these results suggest that the use of improved model parameters can lead to more predictive binding estimates, and that these estimates can be obtained with significantly less computer time than previously thought. These findings make such direct methods more attractive for use in rational drug design.

Metal-induced gap states at well defined alkali-halide/metal interfaces.

In order to search for states specific to insulator/metal interfaces, we have studied epitaxially grown interfaces with element-selective near edge x-ray absorption fine structure. An extra peak is observed below the bulk edge onset for LiCl films on Cu and Ag substrates. The nature of chemical bonds as probed by x-ray photoemission spectroscopy and Auger electron spectroscopy remains unchanged, so we regard this as evidence for metal-induced gap states (MIGS) formed by the proximity to a metal, rather than local bonds at the interface. The dependence on the film thickness shows that the MIGS are as thin as one monolayer. An ab initio electronic structure calculation supports the existence of the MIGS that are strongly localized at the interface.