A quantum mechanical polarizable force field for biomolecular interactions

Abstract

We introduce a quantum mechanical polarizable force field (QMPFF) fitted solely to QM data at the MP2͞aTZ(-hp) level. Atomic charge density is modeled by point-charge nuclei and floating exponentially shaped electron clouds. The functional form of interaction energy parallels quantum mechanics by including electrostatic, exchange, induction, and dispersion terms. Separate fitting of each term to the counterpart calculated from high-quality QM data ensures high transferability of QMPFF parameters to different molecular environments, as well as accurate fit to a broad range of experimental data in both gas and liquid phases. QMPFF, which is much more efficient than ab initio QM, is optimized for the accurate simulation of biomolecular systems and the design of drugs.drug design ͉ quantum mechanics A ccurate simulation of intermolecular interactions is essential in computational studies of chemical and biological systems ranging from multimer spectroscopy in molecular beams, atomsurface interactions, and catalyzed chemical reactions to protein folding and rational drug design. The most reliable and consistent means for such simulations would be to directly use quantum mechanics. However, this is much too computationally demanding, mandating instead the use of a force field, in which the molecular potential surface is approximated by simple analytical formulas. Commonly used force fields including CHARMM, OPLS-AA, MMFF, and AMBER (1-4) originated with Lifson's and Warshel's (5) consistent force field; they all use two basic types of interactions, bonded and nonbonded. The bonded terms are usually modeled formally as functions of stretching, bending, and torsion, whereas the nonbonded components are more physically grounded and involve electrostatic and van der Waals potentials. Electrostatics is described in terms of fixed point charges, and the van der Waals interaction is usually approximated by the classical Leonard-Jones ''12-6'' potential or its modifications. Empirical parameters that shape the various functional forms are found by fitting to low-level quantum mechanical (QM) and͞or experimental data for simple molecules and their interactions in the solid and liquid phases.Although such force fields have been quite successful in modeling a wide variety of molecular systems, there are significant problems in simulation of liquid-phase solutes (6). These force fields have many possible defects including oversimplified treatment of bonded interactions and approximation of charge distributions by point charges with consequent neglect of charge penetration effects, nonadiabatic motions, and other QM features of intra-and intermolecular interactions. However, the most serious defect is recognized to be the failure to incorporate electronic polarization at a fundamental level, which is especially important in a polar medium such as water. To allow for the effects of polarization, the standard nonpolarizable force fields fit the mean field of the liquid by artificially increased dipole moments, deformed molecular geo...

Water properties from first principles: Simulations by a general-purpose quantum mechanical polarizable force field

“…14, except for the diffusion constant taken from ref. 15. As seen, the QMPFF2 classical MD results are close to the experimental values.…”

“…5). The restraint potential provided by the spring is close to harmonic at small distances, but the stiffness becomes infinite as the distance approaches a limiting value, thus preventing the ''polarization catastrophe'' (15). For QMPFF1 the induction term is isotropic, whereas for QMPFF2 it is anisotropic (see Eq.…”

“…ref. 15 and Tables 4 and 5, which are published as supporting information on the PNAS web site. To accommodate the more refined functional forms of the QMPFF2 nonbonded interactions, each atom type requires eight parameters, and each general bond type requires five parameters (two parameters for symmetric bonds).…”

“…ref. 15 and Eqs. 6 and 7 in Supporting Text, which is published as supporting information on the PNAS web site.…”

“…QMPFF1 accurately simulates the interactions in many organic complexes (15). In this article we present the results of classical and PIMD simulations of liquid water by using a second, more refined version of the force field, QMPFF2.…”