Search

A novel method is presented for fitting force-field dihedral angles using an ensemble of structures generated from an ab initio Monte Carlo simulation. Importance sampling is used to achieve an efficient algorithm using a low level of theory to minimize the system at each step with the dihedral angles constrained, followed by dihedral fitting using the single point energies at a higher level of theory. The resulting method is an order of magnitude more efficient than the traditional method of doing a constrained scan over each dihedral independently. Also as the sampling is more uniformly distributed, the full surface is approximated to a greater accuracy. The dihedral fitting is done with a nonlinear optimization method to vary the phase as well as the force constant. The utility of the method is demonstrated by fitting dihedrals of methyl L-lactate, diisopropyl fluorophosphate, isopentenyl phosphate, a leucine dipeptide, and two inhibitors of Signal Transducer and Activator of Transcription 5. The results show that the Monte Carlo scheme is more efficient than constrained scans and is particularly effective at approximating the underlying potential energy surface when the dihedral degrees are coupled. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Due to the computational cost involved, when developing a force field for new compounds, one often avoids fitting van der Waals (vdW) terms, instead relying on a general force field based on the atom type. Here, we provide a novel approach to efficiently optimize vdW terms, based on both ab initio dimer energies and condensed phase properties. The approach avoids the computational challenges of searching the parame-ter space by using an extrapolation method to obtain a reliable difference quotient for the parameter derivatives based on the central difference. The derivatives are then used in an active-space optimization method which convergences quadratically. This method is applicable to polarizable and nonpolarizable force fields, although we focus on the parameterization of the AMBER force field. The scaling of the electrostatic potential ESP) of the compounds is also studied. The algorithm is tested on 12 compounds, reducing the root mean squared error (RMSE) of the density from 0.061 g/cm³ with GAFF parameters to 0.004 g/cm³, and the heat of vaporization from 1.13 to 0.05 kcal/mol. This is done with only four iterations of molecular dynamic runs. Using the optimized vdW parameters, the RMSE of the self-diffusion (Dself) was reduced from 1.22 X 10-9 to 0.78 X 10-9 m² s-1 and the RMSE of the hydration free energies (ΔGsolv) was reduced from 0.30 to 0.26 kcal/mol. Scaling the ESP to improve dimer energies resulted in the Dself RMSE improving to 0.77X 10-9 m² s-1 but the ΔGsolv worsened to 0.33 kcal/mol. [ABSTRACT FROM AUTHOR]