POSSIM: Parameterizing Complete Second-Order Polarizable Force Field for Proteins.

Previously, we reported development of a fast polarizable force field and software named POSSIM (POlarizable Simulations with Second order Interaction Model). The second-order approximation permits the speed up of the polarizable component of the calculations by ca. an order of magnitude.

Effects of lysine substitution on stability of polyalanine alpha-helix.

We have studied stability of polyalanine alpha-helices with lysine residues added at C-and N-termini in gas-phase and aqueous solution. Monte Carlo simulations with the fixed-charges OPLS-AA and our polarizable POSSIM force fields were carried out. The results of the simulations confirm previously observed phenomena of the helix being stable with the LYS residue on the C-terminus and losing its helical structure if the charged LYS residue is located at the N-terminus of the polypeptide in gas-hase.

Polarizable simulations with second order interaction model (POSSIM) force field: developing parameters for protein side-chain analogues.

A previously introduced polarizable simulations with second-order interaction model (POSSIM) force field has been extended to include parameters for small molecules serving as models for peptide and protein side-chains. Parameters have been fitted to permit reproducing many-body energies, gas-phase dimerization energies, and geometries and liquid-phase heats of vaporization and densities. Quantum mechanical and experimental data have been used as the target for the fitting.

Importance of electrostatic polarizability in calculating cysteine acidity constants and copper(I) binding energy of Bacillus subtilis CopZ.

CopZ is a copper chaperone from Bacillus subtilis. It is an important part of Cu(I) trafficking. We have calculated pK(a) values for the CXXC motif of this protein, which is responsible for the Cu(I) binding, and the Cu(I) binding constants.

Electrostatic polarization is crucial in reproducing Cu(I) interaction energies and hydration.

We have explored the suitability of fixed-charges and polarizable force fields for modeling interactions of the monovalent Cu(I) ion. Parameters for this ion have been tested and refitted within the fixed-charges OPLS-AA and polarizable force field (PFF) frameworks. While this ion plays an important role in many protein interactions, the attention to it in developing empirical force fields is limited.

Polarizable Simulations with Second order Interaction Model (POSSIM) force field: Developing parameters for alanine peptides and protein backbone.

A previously introduced POSSIM (POlarizable Simulations with Second order Interaction Model) force field has been extended to include parameters for alanine peptides and protein backbones. New features were introduced into the fitting protocol, as compared to the previous generation of the polarizable force field for proteins. A reduced amount of quantum mechanical data was employed in fitting the electrostatic parameters.

Computational prediction and analysis of the DR6-NAPP interaction.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that involves a devastating clinical course and that lacks an effective treatment. A biochemical model for neuronal development, recently proposed by Nikolaev et al., that may also have implications for AD, hinges on a novel protein–protein interaction between the death cell receptor 6 (DR6) ectodomain and an Nterminal fragment of amyloid precursor protein (NAPP), specifically, the growth factor-like domain of NAPP (GFD NAPP).

Polarizable Simulations with Second order Interaction Model - force field and software for fast polarizable calculations: Parameters for small model systems and free energy calculations.

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.

Relaxation dynamics of nucleosomal DNA.

Recent experimental and theoretical evidence demonstrates that proteins and water in the hydration layer can follow complex stretched exponential or power law relaxation dynamics. Here, we report on a 50 ns all atom molecular dynamics (MD) simulation of the yeast nucleosome, where the interactions between DNA, histones, surrounding water and ions are explicitly included. DNA interacts with the histone core in 14 locations, approximately every 10.

Dynamics of water and ions near DNA: comparison of simulation to time-resolved stokes-shift experiments.

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 [ Andreatta, D.

Spectroscopic and molecular dynamics evidence for a sequential mechanism for the A-to-B transition in DNA.

The A-to-B form transition has been examined in three DNA duplexes, d(CGCGAATTCGCG)(2), d(CGCGAATTGCGC), and d(CGCAAATTTCGC), using circular dichroism spectroscopy, ultraviolet resonance Raman (UVRR) spectroscopy, and molecular dynamics (MD) simulation. Circular dichroism spectra confirm that these molecules adopt the A form under conditions of reduced water activity. UVRR results, obtained under similar conditions, suggest that the transition involves a series of intermediate forms between A and B.

Root mean square deviation probability analysis of molecular dynamics trajectories on DNA.

The comparison and detection of the commonalities and differences in multiple structural ensembles is an important step in the use of molecular simulations to gain insight into the conformation and dynamics of complex biomacromolecules. While the average structure is often employed as the representative of an ensemble of structures in such comparisons, dynamic molecular systems with multiple conformational substates call for a more accurate representation that captures the complete dynamical range of the ensemble. We present a probability analysis procedure based on the root-mean-square differences among the structural ensembles that efficiently and accurately performs the relevant comparison.

Ion motions in molecular dynamics simulations on DNA.

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.