The classical transition state theory (TST), together with the notion of transmission coefficient, provides a useful tool for calculation of rate constants for rare events. However, in complex biomolecular reactions, such as protein folding, it is difficult to find a good reaction coordinate, so the transition state is ill-defined. In this case, other approaches are more popular, such as the transition interface sampling (TIS) and the forward flux sampling (FFS).
View Article and Find Full Text PDFWe propose a new approach to calculate the conformational free energy of a macromolecule in a compact stable state in implicit solvent. The free energy is evaluated with respect to an artificial reference system without internal interactions that is confined to a small well-defined multidimensional volume of a regular shape occupying approximately the same part of the conformational space as the macromolecule of interest. We present a practical implementation of our method, successfully apply it to a β-hairpin in all-atom representation, verify the results with direct parallel tempering simulations, and discuss the possibilities of further improvements.
View Article and Find Full Text PDFStud Health Technol Inform
September 2012
The Collaborative Computing Project for NMR (CCPN) has build a software framework consisting of the CCPN data model (with APIs) for NMR related data, the CcpNmr Analysis program and additional tools like CcpNmr FormatConverter. The open architecture allows for the integration of external software to extend the abilities of the CCPN framework with additional calculation methods. Recently, we have carried out the first steps for integrating our software Computer Simulation of Molecular Structures (COSMOS) into the CCPN framework.
View Article and Find Full Text PDFWe propose a new type of transition network for modeling of protein dynamics. The nodes of the network correspond to the conformations taken from random sampling of equilibrium ensemble available, e.g.
View Article and Find Full Text PDFThe computational effort of biomolecular simulations can be significantly reduced by means of implicit solvent models in which the energy generally contains a correction depending on the surface area and/or the volume of the molecule. In this article, we present simple derivation of exact, easy-to-use analytical formulas for these quantities and their derivatives with respect to atomic coordinates. In addition, we provide an efficient, linear-scaling algorithm for the construction of the power diagram required for practical implementation of these formulas.
View Article and Find Full Text PDFBiochim Biophys Acta
August 2011
In the last decades biomolecular simulation has made tremendous inroads to help elucidate biomolecular processes in-silico. Despite enormous advances in molecular dynamics techniques and the available computational power, many problems involve long time scales and large-scale molecular rearrangements that are still difficult to sample adequately. In this review we therefore summarise recent efforts to fundamentally improve this situation by decoupling the sampling of the energy landscape from the description of the kinetics of the process.
View Article and Find Full Text PDFWe present a novel and efficient method for computation of rate constants in the systems where two metastable states are separated by a high free energy barrier. Our approach is based on the thermodynamic integration applied to the grand canonical ensemble of the stochastic transition paths. As illustrated on a multidimensional model system, the required computational costs depend only weakly on the barrier height, which provides a speedup of orders of magnitude in comparison to direct simulations.
View Article and Find Full Text PDFNanomechanical properties of filamentous biopolymers, such as the persistence length, may be determined from two-dimensional images of molecules immobilized on surfaces. For a single filament in solution, two principal adsorption scenarios are possible. Both scenarios depend primarily on the interaction strength between the filament and the support: i) For interactions in the range of the thermal energy, the filament can freely equilibrate on the surface during adsorption; ii) For interactions much stronger than the thermal energy, the filament will be captured by the surface without having equilibrated.
View Article and Find Full Text PDFModulation of protein-protein interactions by competitive small-molecule binding emerges as a promising avenue for drug discovery. Hot spots, i.e.
View Article and Find Full Text PDFBiophysical forcefields have contributed less than originally anticipated to recent progress in protein structure prediction. Here, we have investigated the selectivity of a recently developed all-atom free-energy forcefield for protein structure prediction and quality assessment (QA). Using a heuristic method, but excluding homology, we generated decoy-sets for all targets of the CASP7 protein structure prediction assessment with <150 amino acids.
View Article and Find Full Text PDFThe recently introduced method of excess collisions to estimate reaction times of protein-DNA systems in the presence of facilitated diffusion ("sliding") requires a cell of full system size. This bottleneck is avoided with a modification, by which a set of empirical parameters is calibrated using numerical simulations of a small test system. Once this is done, reaction times for systems of arbitrary dimensions are derived by extrapolation.
View Article and Find Full Text PDFIn this paper, a new method to efficiently simulate diffusion controlled second order chemical reactions is derived and applied to site-specific DNA-binding proteins. The protein enters a spherical cell and propagates via two competing modes, a free diffusion and a DNA-sliding mode, to search for its specific binding site in the center of the cell. There is no need for a straightforward simulation of this process.
View Article and Find Full Text PDFThe diffusion-controlled limit of reaction times for site-specific DNA-binding proteins is derived from first principles. We follow the generally accepted concept that a protein propagates via two competitive modes, a three-dimensional diffusion in space and a one-dimensional sliding along the DNA. However, our theoretical treatment of the problem is new.
View Article and Find Full Text PDFIt is well documented that diffusion has generally a strong effect on the binding kinetics in the microtiter plate immunoassays. However, a systematic quantitative experimental evaluation of the microspot kinetics is still missing in the literature. Our work aims at filling this important gap of knowledge on the example of antigen binding to antibody microspots.
View Article and Find Full Text PDFIn a solid-phase immunoassay, binding between an antigen and its specific antibody takes place at the boundary of a liquid and a solid phase. One of the reactants (receptor) is immobilized on a surface. The other reactant (ligand) is initially free in solution.
View Article and Find Full Text PDFBy the traditional approach to the Brownian dynamics simulations of intrachain reactions of polymers, the initial chain conformation is sampled from the equilibrium distribution. A dynamic trajectory is carried out until a "collision" of the reactive groups takes place, i.e.
View Article and Find Full Text PDFA curved DNA segment is known to adopt a preferred end loop localization in superhelical (sc) DNA and thus may organize the overall conformation of the molecule. Through this process it influences the probability of site juxtaposition. We addressed the effect of a curvature on site-site interactions quantitatively by measuring the kinetics of cross-linking of two biotinylated positions in scDNA by streptavidin.
View Article and Find Full Text PDFIt was found recently that bacterial type II DNA topoisomerase, topo IV, is much more efficient in relaxing (+) DNA supercoiling than (-) supercoiling. This means that the DNA-enzyme complex is chiral. This chirality can appear upon binding the first segment that participates in the strand passing reaction (G segment) or only after the second segment (T segment) joins the complex.
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