Symmetrization of the AMBER and CHARMM force fields.

The AMBER and CHARMM force fields are analyzed from the viewpoint of the permutational symmetry of the potential for feasible exchanges of identical atoms and chemical groups in amino and nucleic acids. In each case, we propose schemes for symmetrizing the potentials, which greatly facilitate the bookkeeping associated with constructing kinetic transition networks via geometry optimization.

Computer Simulations of Peptides from the p53 DNA Binding Domain.

We have studied the dynamics and thermodynamics of two of the four evolutionarily conserved segments from the p53 DNA binding domain, using molecular dynamics and replica exchange simulations. These two regions contain well-defined elements of secondary structure (a β hairpin for region II and an α helix for region V) and bind to DNA in the intact protein. They are also mutational hot spots.

Pathways for conformational change in nitrogen regulatory protein C from discrete path sampling.

Pathways corresponding to the conformational change in nitrogen regulatory protein C are calculated using the CHARMM19 force field with an implicit solvation model. Our analysis employs the discrete path sampling approach to grow a database of local minima and transition states from the potential energy surface that contains kinetically relevant pathways. The pathways with the largest contribution to the phenomenological two-state rate constants are found to exhibit a number of structural features that agree with experimental observations.

Modification and optimization of the united-residue (UNRES) potential energy function for canonical simulations. I. Temperature dependence of the effective energy function and tests of the optimization method with single training proteins.

We report the modification and parametrization of the united-residue (UNRES) force field for energy-based protein structure prediction and protein folding simulations. We tested the approach on three training proteins separately: 1E0L (beta), 1GAB (alpha), and 1E0G (alpha + beta). Heretofore, the UNRES force field had been designed and parametrized to locate native-like structures of proteins as global minima of their effective potential energy surfaces, which largely neglected the conformational entropy because decoys composed of only lowest-energy conformations were used to optimize the force field.

Protein-folding dynamics: overview of molecular simulation techniques.

Molecular dynamics (MD) is an invaluable tool with which to study protein folding in silico. Although just a few years ago the dynamic behavior of a protein molecule could be simulated only in the neighborhood of the experimental conformation (or protein unfolding could be simulated at high temperature), the advent of distributed computing, new techniques such as replica-exchange MD, new approaches (based on, e.g.

Molecular dynamics with the united-residue model of polypeptide chains. II. Langevin and Berendsen-bath dynamics and tests on model alpha-helical systems.

The implementation of molecular dynamics (MD) with our physics-based protein united-residue (UNRES) force field, described in the accompanying paper, was extended to Langevin dynamics. The equations of motion are integrated by using a simplified stochastic velocity Verlet algorithm. To compare the results to those with all-atom simulations with implicit solvent in which no explicit stochastic and friction forces are present, we alternatively introduced the Berendsen thermostat.

Molecular dynamics with the united-residue model of polypeptide chains. I. Lagrange equations of motion and tests of numerical stability in the microcanonical mode.

The Lagrange formalism was implemented to derive the equations of motion for the physics-based united-residue (UNRES) force field developed in our laboratory. The C(alpha)..

A localized specific interaction alters the unfolding pathways of structural homologues.

Reductive unfolding studies of proteins are designed to provide information about intramolecular interactions that govern the formation (and stabilization) of the native state and about folding/unfolding pathways. By mutating Tyr92 to G, A, or L in the model protein, bovine pancreatic ribonuclease A, and through analysis of temperature factors and molecular dynamics simulations of the crystal structures of these mutants, it is demonstrated that the markedly different reductive unfolding rates and pathways of ribonuclease A and its structural homologue onconase can be attributed to a single, localized, ring-stacking interaction between Tyr92 and Pro93 in the bovine variant. The fortuitous location of this specific stabilizing interaction in a disulfide-bond-containing loop region of ribonuclease A results in the localized modulation of protein dynamics that, in turn, enhances the susceptibility of the disulfide bond to reduction leading to an alteration in the reductive unfolding behavior of the homologues.

Kinetic studies of folding of the B-domain of staphylococcal protein A with molecular dynamics and a united-residue (UNRES) model of polypeptide chains.

Langevin dynamics is used with our physics-based united-residue (UNRES) force field to study the folding pathways of the B-domain of staphylococcal protein A (1BDD (alpha; 46 residues)). With 400 trajectories of protein A started from the extended state (to gather meaningful statistics), and simulated for more than 35 ns each, 380 of them folded to the native structure. The simulations were carried out at the optimal folding temperature of protein A with this force field.

Ab initio simulations of protein-folding pathways by molecular dynamics with the united-residue model of polypeptide chains.

We report the application of Langevin dynamics to the physics-based united-residue (UNRES) force field developed in our laboratory. Ten trajectories were run on seven proteins [PDB ID codes 1BDD (alpha; 46 residues), 1GAB (alpha; 47 residues), 1LQ7 (alpha; 67 residues), 1CLB (alpha; 75 residues), 1E0L (beta; 28 residues), and 1E0G (alpha+beta; 48 residues), and 1IGD (alpha+beta; 61 residues)] with the UNRES force field parameterized by using our recently developed method for obtaining a hierarchical structure of the energy landscape. All alpha-helical proteins and 1E0G folded to the native-like structures, whereas 1IGD and 1E0L yielded mostly nonnative alpha-helical folds although the native-like structures are lowest in energy for these two proteins, which can be attributed to neglecting the entropy factor in the current parameterization of UNRES.

A united residue force-field for calcium-protein interactions.

United-residue potentials are derived for interactions of the calcium cation with polypeptide chains in energy-based prediction of protein structure with a united-residue (UNRES) force-field. Specific potentials were derived for the interaction of the calcium cation with the Asp, Glu, Asn, and Gln side chains and the peptide group. The analytical expressions for the interaction energies for each of these amino acids were obtained by averaging the electrostatic interaction energy, expressed by a multipole series over the dihedral angles not considered in the united-residue model, that is, the side-chain dihedral angles chi and the dihedral angles lambda for the rotation of peptide groups about the C(alpha).