Electrostatic screening in molecular dynamics simulations

The screened Coulombic potential has been shown to describe satisfactorily equilibrium properties like pK shifts, the effects of charged groups on redox potentials and binding constants of metal ions. To test how well the screening of the electrostatic potential describes the dynamical trajectory of a macromolecular system, a series of comparative simulations have been carried out on a protein system which explicitly included water molecules and a system in vacuo. For the system without solvent the results of using (i) the standard potential form were compared with results of (ii) the potential where the Coulomb term was modified by the inclusion of a distance dependent dielectric, ε(r), to model the screening effect of bulk water, and (iii) standard potential modified by reducing the charge on ionized residue side chains. All molecular dynamics simulations have been carried out on bovine pancreatic trypsin inhibitor. Comparisons between the resulting trajectories, averaged structures, hydrogen bonding patterns and properties such as solvent accessible surface area and radius of gyration are described. The results show that the dynamical behaviour of the protein calculated with a screened electrostatic term compares more favourably with the time-dependent structural changes of the full system with explicitly included water than the standard vacuum simulatio

Electrostatic effects in proteins: comparison of dielectric and charge models

Two approaches for calculating electrostatic effects in proteins are compared and an analysis is presented of the dependence of calculated properties on the model used to define the charge distribution. Changes in electrostatic free energy have been calculated using a screened Coulomb potential (SCP) with a distance-dependent effective dielectric permittivity to model bulk solvent effects and a finite difference approach to solve the Poisson-Boltzmann (FDPB) equation. The properties calculated include shifts in dissociation constants of ionizable groups, the effect of annihilating surface charges on the binding of metals, and shifts in redox potentials due to changes in the charge of ionizable groups. In the proteins considered the charged sites are separated by 3.5-12 Å. It is shown that for the systems studied in this distance range the SCP yields calculated values which are at least as accurate as those obtained from solution of the FDPB equation. In addition, in the distance range 3-5 Å the SCP gives substantially better results than the FDPB equation. Possible sources of this difference between the two methods are discussed. Shifts in binding constants and redox potentials were calculated with several standard charge sets, and the resulting values show a variation of 20-40% between the best and worst cases. From this study it is concluded that in most applications, changes in electrostatic free energies can be calculated economically and reliably using an SCP approach with a single functional form of the screening functio

Local Simulation Algorithms for Coulomb Interaction

Long ranged electrostatic interactions are time consuming to calculate in molecular dynamics and Monte-Carlo simulations. We introduce an algorithmic framework for simulating charged particles which modifies the dynamics so as to allow equilibration using a local Hamiltonian. The method introduces an auxiliary field with constrained dynamics so that the equilibrium distribution is determined by the Coulomb interaction. We demonstrate the efficiency of the method by simulating a simple, charged lattice gas.Comment: Last figure changed to improve demonstration of numerical efficienc

Use of distance geometry approach for the in vitro antiviral activity evaluation of N-bridgehead C-nucleosides

We have used a 3-dimensional receptor model of parainfluenza virus type 3 developed by Ghose et al using the distance geometry approach to analyze the in vitro antiviral activity of several novel ribonucleosides from imidazotriazine, imidazo-pyrazine and triazolo-pyrazine and pyridine series. On the basis of atomic physicochemical properties ie hydrophobicity, molar refractivity and charge density the interaction energy of minimum energy conformations of 22 compounds with hypothetic virus active site were evaluated. Seven nucleosides from imidazo-pyrazine and imidazo-triazine series have shown significantly high calculated values of virus rating while the analogues with triazolopyrazine, triazolo-pyridine and pyrazolo-pyridine heterocycles are expected to have only slight or moderate virus activity