A Central Partition of Molecular Conformational Space.III. Combinatorial Determination of the Volume Spanned by a Molecular System

In the first work of this series [physics/0204035] it was shown that the conformational space of a molecule could be described to a fair degree of accuracy by means of a central hyperplane arrangement. The hyperplanes divide the espace into a hierarchical set of cells that can be encoded by the face lattice poset of the arrangement. The model however, lacked explicit rotational symmetry which made impossible to distinguish rotated structures in conformational space. This problem was solved in a second work [physics/0404052] by sorting the elementary 3D components of the molecular system into a set of morphological classes that can be properly oriented in a standard 3D reference frame. This also made possible to find a solution to the problem that is being adressed in the present work: for a molecular system immersed in a heat bath we want to enumerate the subset of cells in conformational space that are visited by the molecule in its thermal wandering. If each visited cell is a vertex on a graph with edges to the adjacent cells, here it is explained how such graph can be built

Dynamics of ions in the selectivity filter of the KcsA channel

The statistical and dynamical properties of ions in the selectivity filter of the KcsA ion channel are considered on the basis of molecular dynamics (MD) simulations of the KcsA protein embedded in a lipid membrane surrounded by an ionic solution. A new approach to the derivation of a Brownian dynamics (BD) model of ion permeation through the filter is discussed, based on unbiased MD simulations. It is shown that depending on additional assumptions, ion’s dynamics can be described either by under-damped Langevin equation with constant damping and white noise or by Langevin equation with a fractional memory kernel. A comparison of the potential of the mean force derived from unbiased MD simulations with the potential produced by the umbrella sampling method demonstrates significant differences in these potentials. The origin of these differences is an open question that requires further clarifications

A Central Partition of Molecular Conformational Space. IV. Extracting information from the graph of cells

In previous works [physics/0204035, physics/0404052, physics/0509126] a procedure was described for dividing the $3 \times N$-dimensional conformational space of a molecular system into a number of discrete cells, this partition allowed the building of a combinatorial structure from data sampled in molecular dynamics trajectories: the graph of cells, that encodes the set of cells in conformational space that are visited by the system in its thermal wandering. Here we outline a set of procedures for extracting useful information from this structure: 1st) interesting regions in the volume occupied by the system in conformational space can be bounded by a polyhedral cone whose faces are determined empirically from a set of relations between the coordinates of the molecule, 2nd) it is also shown that this cone can be decomposed into a hierarchical set of smaller cones, 3rd) the set of cells in a cone can be encoded by a simple combinatorial sequence.Comment: added an intrduction and reference

Progress toward chemcial accuracy in the computer simulation of condensed phase reactions

A procedure is described for the generation of chemically accurate computer-simulation models to study chemical reactions in the condensed phase. The process involves (1) the use of a coupled semiempirical quantum and classical molecular mechanics method to represent solutes and solvent, respectively; (2) the optimization of semiempirical quantum mechanics (QM) parameters to produce a computationally efficient and chemically accurate QM model; (3) the calibration of a quantum/classical microsolvation model using ab initio quantum theory; and (4) the use of statistical mechanical principles and methods to simulate, on massively parallel computers, the thermodynamic properties of chemical reactions in aqueous solution. The utility of this process is demonstrated by the calculation of the enthalpy of reaction in vacuum and free energy change in aqueous solution for a proton transfer involving methanol, methoxide, imidazole, and imidazolium, which are functional groups involved with proton transfers in many biochemical systems. An optimized semiempirical QM model is produced, which results in the calculation of heats of formation of the above chemical species to within 1.0 kcal/mol of experimental values. The use of the calibrated QM and microsolvation QM/MM models for the simulation of a proton transfer in aqueous solution gives a calculated free energy that is within 1.0 kcal/mol (12.2 calculated vs. 12.8 experimental) of a value estimated from experimental pKa`s of the reacting species

Molecular dynamics study of accelerated ion-induced shock waves in biological media

We present a molecular dynamics study of the effects of carbon- and iron-ion induced shock waves in DNA duplexes in liquid water. We use the CHARMM force field implemented within the MBN Explorer simulation package to optimize and equilibrate DNA duplexes in liquid water boxes of different sizes and shapes. The translational and vibrational degrees of freedom of water molecules are excited according to the energy deposited by the ions and the subsequent shock waves in liquid water are simulated. The pressure waves generated are studied and compared with an analytical hydrodynamics model which serves as a benchmark for evaluating the suitability of the simulation boxes. The energy deposition in the DNA backbone bonds is also monitored as an estimation of biological damage, something which is not possible with the analytical model

Філософія популізму як варіант сучасної філософії

We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections

Molecular Modeling of Nucleic Acid Structure: Setup and Analysis

The last in a set of units by these authors, this unit addresses some important remaining questions about molecular modeling of nucleic acids. It describes how to choose an appropriate molecular mechanics force field; how to set up and equilibrate the system for accurate simulation of a nucleic acid in an explicit solvent by molecular dynamics or Monte Carlo simulation; and how to analyze molecular dynamics trajectories.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153007/1/cpnc0710.pd