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

Abstract

Charges derived from fitting a classical Coulomb model to quantum mechanical molecular electrostatic potentials (so called ESP-charges) are frequently used in simulations of macromolecules. Simulational methods that use ESP-charges generally reproduce the geometries of hydrogen bonded complexes, despite the fact that these charges are known to overestimate the strengths of these interactions. Through the use of a restraint function during the fitting of the partial charges to the electrostatic potentials the magnitudes of the charges may be attenuated (so called RESP-charges). For the AMBER force field RESP-charges have been proposed for proteins and nucleic acids. Here we examine a novel approach for determining the RESP-charges for carbohydrates 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 the suitability of a set of partial charges by monitoring the properties of the crystal during an MD simulation. We have examined several charge sets for use with the GLYCAM parameters for carbohydrate and glycoprotein simulations and found that a restraint weight of 0.01 gives the best agreement with the neutron diffraction structure of α-D-glucopyranose. Unrestrained ESP-charges performed poorly as did the charges obtained from Mulliken and distributed multipole analyses of the quantum mechanical HF/6-31G* wavefunctions.

Relative Energies of Binding for Antibody−Carbohydrate-Antigen Complexes Computed from Free-Energy Simulations

“…On the basis of simulations of condensed phase crystals of carbohydrates and by employing several parameter sets, we believe it is the latter that is responsible for the poor performance of the ESP-charge model. 39 The use of lower magnitude partial atomic charges in the RESP model restores the agreement with experiment and is further support for the hypothesis that the ESP-charges lead to excessive O-O repulsions between the protein and the carbohydrate. The current simulations are based on the crystal structure of the sc-Fv antibody fragment, whereas the thermodynamic data were acquired with the Fab fragment.…”

Empirical force fields for biological macromolecules: Overview and issues

“…298 Glennon and Merz developed an hexapyronse force field in which semiempirical calculations were used to assign partial atomic charges to each atom (vs. all secondary hydroxyls having the same charge). 299,300 Woods and coworkers have developed the GLY-CAM force field 301 again by considering the unique partial atomic charges for the individual atoms, including ensemble averaging in the charge determination 302,303 as well as additional optimization of internal parameters. Recent updates of the GLYCAM force field have included use of a 1,4 scale factor of 1.0 304 vs. 1/1.2 common to the remainder of the AMBER force fields and a general carbohydrate model that avoids anomeric carbon specific terms is available (R. Woods, personal communication).…”

Approach for the Simulation and Modeling of Flexible Rings: Application to the α-d-Arabinofuranoside Ring, a Key Constituent of Polysaccharides from Mycobacterium tuberculosis

“…The value of the RESP restraint weight was set to 0.01, and fitting was performed on all of the atoms except the aliphatic hydrogen. 45 The second charge derivation procedure is an important result of the current report and is described in the following section.…”