Thomas A. Halgren

Integrated Modeling Program, Applied Chemical Theory (IMPACT)

We provide an overview of the IMPACT molecular mechanics program with an emphasis on recent developments and a description of its current functionality. With respect to core molecular mechanics technologies we include a status report for the fixed charge and polarizable force fields that can be used with the program and illustrate how the force fields, when used together with new atom typing and parameter assignment modules, have greatly expanded the coverage of organic compounds and medicinally relevant ligands. As we discuss in this review, explicit solvent simulations have been used to guide our design of implicit solvent models based on the generalized Born framework and a novel nonpolar estimator that have recently been incorporated into the program. With IMPACT it is possible to use several different advanced conformational sampling algorithms based on combining features of molecular dynamics and Monte Carlo simulations. The program includes two specialized molecular mechanics modules: Glide, a high‐throughput docking program, and QSite, a mixed quantum mechanics/molecular mechanics module. These modules employ the IMPACT infrastructure as a starting point for the construction of the protein model and assignment of molecular mechanics parameters, but have then been developed to meet specialized objectives with respect to sampling and the energy function.

Polarizable force fields.

Standard force fields used in biomolecular computing describe electrostatic interactions in terms of fixed, usually atom-centered, charges. Real physical systems, however, polarize substantially when placed in a high-dielectric medium such as water--or even when a strongly charged system approaches a neutral body in the gas phase. Such polarization strongly affects the geometry and energetics of molecular recognition. First introduced more than 20 years ago, polarizable force fields seek to account for appropriate variations in charge distribution with dielectric environment. Over the past five years, an accelerated pace of development of such force fields has taken place on systems ranging from liquid water to metalloenzymes. Noteworthy progress has been made in better understanding the capabilities and limitations of polarizable models for water and in the formulation and utilization of complete specifically parameterized polarizable force fields for peptides and proteins.

Development of a polarizable force field for proteins via ab initio quantum chemistry: First generation model and gas phase tests

We present results of developing a methodology suitable for producing molecular mechanics force fields with explicit treatment of electrostatic polarization for proteins and other molecular system of biological interest. The technique allows simulation of realistic‐size systems. Employing high‐level ab initio data as a target for fitting allows us to avoid the problem of the lack of detailed experimental data. Using the fast and reliable quantum mechanical methods supplies robust fitting data for the resulting parameter sets. As a result, gas‐phase many‐body effects for dipeptides are captured within the average RMSD of 0.22 kcal/mol from their ab initio values, and conformational energies for the di‐ and tetrapeptides are reproduced within the average RMSD of 0.43 kcal/mol from their quantum mechanical counterparts. The latter is achieved in part because of application of a novel torsional fitting technique recently developed in our group, which has already been used to greatly improve accuracy of the peptide conformational equilibrium prediction with the OPLS‐AA force field. 1 Finally, we have employed the newly developed first‐generation model in computing gas‐phase conformations of real proteins, as well as in molecular dynamics studies of the systems. The results show that, although the overall accuracy is no better than what can be achieved with a fixed‐charges model, the methodology produces robust results, permits reasonably low computational cost, and avoids other computational problems typical for polarizable force fields. It can be considered as a solid basis for building a more accurate and complete second‐generation model.

Self‐consistent‐field wavefunctions for complex molecules. The approximation of partial retention of diatomic differential overlap

A new approach, based on partial retention of diatomic differential overlap over an orthogonalized basis, is described for approximating LCAO SCF molecular orbital wavefunctions at the minimum basis set level for closed‐shell molecules containing hydrogen and first‐row atoms. The SCF equations are solved explicitly, retaining all one‐electron integrals and approximating two‐electron Coulomb integrals, hybrid integrals, and exchange integrals of the forms (iAjA | iAjA) and (iAjB | jAjB) for centers A and B. Single‐center averaging processes otherwise required for rotational invariance are avoided by the use of local atomic‐centered axes which are unique in anisotropic environments. The result is accuracy comparable to that of much more elaborate methods such as STO‐3G, in computing times only moderately longer than for simpler methods based on neglect of differential overlap such as CNDO and INDO. Both unparameterized and parameterized methods are reported. Comparison of parameterized results with ab initi...

A Polarizable Force Field and Continuum Solvation Methodology for Modeling of Protein-Ligand Interactions

A polarizable force field, and associated continuum solvation model, have been developed for the explicit purpose of computing and studying the energetics and structural features of protein binding to the wide range of ligands with potential for medicinal applications. Parameters for the polarizable force field (PFF) are derived from gas-phase ab initio calculations and then utilized for applications in which the protein binding to ligands occurs in aqueous solvents, wherein the charge distributions of proteins and ligands can be dramatically altered. The continuum solvation model is based on a self-consistent reaction field description of solvation, incorporating an analytical gradient, that allows energy minimizations (and, potentially, molecular dynamics simulations) of protein/ligand systems in continuum solvent. This technology includes a nonpolar model describing the cost of cavity formation, and van der Waals interactions, between the continuum solvent and protein/ligand solutes. Tests of the structural accuracy and computational stability of the methodology, and timings for energy minimizations of proteins and protein/ligand systems in the condensed phase, are reported. In addition, the derivation of polarizability, electrostatic, exchange repulsion, and torsion parameters from ab initio data is described, along with the use of experimental solvation energies for determining parameters for the solvation model.