Restrained electrostatic potential atomic partial charges for condensed-phase simulations of carbohydrates

Charges derived from fitting a classical Coulomb model to quantum mechanica l molecular electrostatic potentials (so called ESP-charges) are frequently used in simulations of macromolecules. Simulational methods that use ESP-c harges generally reproduce the geometries of hydrogen bonded complexes, des pite the fact that these charges are known to overestimate the strengths of these interactions. Through the use of a restraint function during the fit ting of the partial charges to the electrostatic potentials the magnitudes of the charges may be attenuated (so called RESP-charges). For the AMBER fo rce field RESP-charges have been proposed for proteins and nucleic acids. H ere we examine a novel approach for determining the RESP-charges for carboh ydrates based on molecular dynamics (MD) simulations of crystal structures. During a simulation, the crystallographic unit cell geometry is sensitive to both inter-molecular non-bonded forces and internal torsional rotations. However, for polar molecules, and specifically carbohydrates, the crystal geometries are particularly sensitive to the set of partial atomic charges employed in the simulation. Thus, given a force field in which the van der Waals and torsion terms are well parameterized, it is possible to assess th e suitability of a set of partial charges by monitoring the properties of t he crystal during an MD simulation. We have examined several charge sets fo r use with the GLYCAM parameters for carbohydrate and glycoprotein simulati ons and found that a restraint weight of 0.01 gives the best agreement with the neutron diffraction structure of alpha-D-glucopyranose. Unrestrained E SP-charges performed poorly as did the charges obtained from Mulliken and d istributed multipole analyses of the quantum mechanical HF/6-31G* wavefunct ions. (C) 2000 Elsevier Science B.V. All rights reserved.