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.

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.

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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.

We have studied the stable sites for Co both on the surface of Si(100) and subsurface using ab initio methods. We show that the most stable surface site for Co is situated in the dimer trenches (the low site). The subsurface sites that we study are all found to be more stable than the most stable surface site. The most stable subsurface site is the under dimer site. The most stable site of all is, however, the dimer vacancy site formed by removing the dimer above the cobalt in the under dimer site.