Counterions play a significant role in DNA structure and function, and molecular dynamics (MD) simulations offer the prospect of detailed description of the dynamical structure of ions at the molecular level. However, the motions of mobile counterions are notably slow to converge in MD on DNA. Obtaining accurate and reliable MD simulations requires knowing just how much sampling is required for convergence of each of the properties of interest. To address this issue, MD on a d(CGCGAATTCGCG) duplex in a dilute aqueous solution of water and 22 Na ؉ counterions was performed until convergence was achieved. The calculated first shell ion occupancies and DNA-Na ؉ radial distribution functions were computed as a function of time to assess convergence, and compared with relaxation times of the DNA internal parameters shift, slide, rise, tilt, roll, and twist. The sequence dependence of fractional occupancies of ions in the major and minor grooves of the DNA is examined, and the possibility of correlation between ion proximity and DNA minor groove widths is investigated. C ounterion structures and motions have been implicated in recent ideas about sequence effects on DNA structure axis curvature and ligand-induced bending (1-7). In each of these theories, the local interactions of ions with polyionic DNA complement the effects described by counterion condensation (CC) theory (8) and the Poisson Boltzmann (PB) equation (9,10). Although the effect of ions and ionic strength on DNA structural and thermodynamics properties are implied from diverse experiments, obtaining a fully detailed molecular model of the ions interacting with DNA based on these results is usually not possible. Oligonucleotide crystal structures reveal only the few ions that are ordered and can be unequivocally assigned. The positions of ions around DNA are generally underdetermined in experiments based on biophysical methods. Recent studies requiring this information have turned to large-scale molecular dynamics (MD) simulations to obtain computational models (11). However, in MD modeling, the complex aggregate of oligonucleotide, water, counterions, and coions is slow to fully stabilize, and ion motions are a rate-determining step in total convergence (12). Current reviews of MD on DNA (12)(13)(14) indicate that all simulations to date are based on considerably shorter trajectories. Therefore, we initiated a project aimed at obtaining demonstrably converged results on ion structures and motions. A related question is the sensitivity of the fast internal motions of the DNA to ion convergence. Our analysis is based on an MD simulation on the prototype B-form duplex d(CGC-GAATTCGCG) in a dilute aqueous solution of water and Na ϩ counterions carried out on a supercomputer until the point of convergence could be reliably determined. The trajectories are used to study the sequence dependence of ion distributions, the DNA-Na ϩ radial distribution functions, and the sensitivity of groove widths to ion proximity. The simulations are used as a basis for a compa...

Time-resolved Stokes-shift experiments measure the dynamics of biomolecules and of the perturbed solvent near them on subnanosecond time scales, but molecular dynamics simulations are needed to provide a clear interpretation of the results. Here we show that simulations using standard methods quantitatively reproduce the main features of TRSS experiments in DNA and provide a molecular assignment for the dynamics. The simulations reproduce the magnitude and unusual power-law dynamics of the Stokes shift seen in recent experiments [D. Andreatta, et al., J. Am. Chem. Soc. 127, 7270 (2005)]. A polarization model is introduced to eliminate cross correlations between the different components contributing to the signal. Using this model, well-defined contributions of the DNA, water and counterion to the experimental signal are extracted. Water is found to have the largest contribution and to be responsible for the power-law dynamics. The counterions have a smaller, but non-negligible contribution with a time constant of 220 ps. The contribution to the signal of the DNA itself is minor and fits a 30 ps stretched exponential. Both time-averaged and dynamic distributions are calculated. They show a small subset of ions with a different coupling, but no other evidence of substates or dynamic heterogeneity.

We are presenting POSSIM (POlarizable Simulations with Second order Interaction Model) – a software package and a set of parameters designed for molecular simulations. The key feature of POSSIM is that the electrostatic polarization is taken into account using a previously introduced fast formalism. This permits cutting computational cost of using the explicit polarization by about an order of magnitude. In this article, parameters for water, methane, ethane, propane, butane, methanol and NMA are introduced. These molecules are viewed as model systems for protein simulations. We have achieved our goal of ca. 0.5 kcal/mol accuracy for gas-phase dimerization energies and no more than 2% deviations in liquid state heats of vaporization and densities. Moreover, free energies of hydration of the polarizable methane, ethane and methanol have been calculated using the statistical perturbation theory. These calculations are a model for calculating protein pKa shifts and ligand binding affinities. The free energies of hydration were found to be 2.12 kcal/mol, 1.80 kcal/mol and −4.95 kcal/mol for methane, ethane and methanol, respectively. The experimentally determined literature values are 1.91 kcal/mol, 1.83 kcal/mol and −5.11 kcal/mol. The POSSIM average error in these absolute free energies of hydration is only about 0.13 kcal/mol. Using the statistical perturbation theory with polarizable force fields is not widespread, and we believe that this work opens road to further development of the POSSIM force field and its applications for obtaining accurate energies in protein-related computer modeling.