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

Glycan Reader: Automated Sugar Identification and Simulation Preparation for Carbohydrates and Glycoproteins

This is the peer reviewed version of the following article: Jo, S., Song, K. C., Desaire, H., MacKerell, A. D., & Im, W. (2011). Glycan Reader: Automated Sugar Identification and Simulation Preparation for Carbohydrates and Glycoproteins. Journal of Computational Chemistry, 32(14), 3135–3141. http://doi.org/10.1002/jcc.21886, which has been published in final form at http://doi.org/10.1002/jcc.21886. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Understanding how glycosylation affects protein structure, dynamics, and function is an emerging and challenging problem in biology. As a first step toward glycan modeling in the context of structural glycobiology, we have developed Glycan Reader and integrated it into the CHARMMGUI, http://www.charmm-gui.org/input/glycan. Glycan Reader greatly simplifies the reading of PDB structure files containing glycans through (i) detection of carbohydrate molecules, (ii) automatic annotation of carbohydrates based on their three-dimensional structures, (iii) recognition of glycosidic linkages between carbohydrates as well as N-/O-glycosidic linkages to proteins, and (iv) generation of inputs for the biomolecular simulation program CHARMM with the proper glycosidic linkage setup. In addition, Glycan Reader is linked to other functional modules in CHARMM-GUI, allowing users to easily generate carbohydrate or glycoprotein molecular simulation systems in solution or membrane environments and visualize the electrostatic potential on glycoprotein surfaces. These tools are useful for studying the impact of glycosylation on protein structure and dynamics

Improving the force field description of tyrosine-choline cation-π interactions : QM investigation of phenol-N(Me)₄⁺ interactions

Cation-pi interactions between tyrosine amino acids and compounds containing N,N,N-trimethylethanolammonium (N(CH3)(3)) are involved in the recognition of histone tails by chromodomains and in the recognition of phosphatidylcholine (PC) phospholipids by membrane-binding proteins. Yet, the lack of explicit polarization or charge transfer effects in molecular mechanics force fields raises questions about the reliability of the representation of these interactions in biomolecular simulations. Here, we investigate the nature of phenol tetramethylammonium (TMA) interactions using quantum mechanical (QM) calculations, which we also use to evaluate the accuracy of the additive CHARIVIM36 and Drude polarizable force fields in modeling tyrosine-choline interactions. We show that the potential energy surface (PES) obtained using SAPT2+/aug-cc-pVDZ compares well with the large basis-set CCSD(T) PES when TMA approaches the phenol ring perpendicularly. Furthermore, the SAPT energy decomposition reveals comparable contributions from electrostatics and dispersion in phenol-TMA interactions. We then compared the SAPT2+/augcc-pVDZ PES obtained along various approach directions to the corresponding PES obtained with CHARMM, and we show that the force field accurately reproduces the minimum distances while the interaction energies are underestimated. The use of the Drude polarizable force field significantly improves the interaction energies but decreases the agreement on distances at energy minima. The best agreement between force field and QM PES is obtained by modifying the Lennard-Jones terms for atom pairs involved in the phenol-TMA cation-pi interactions. This is further shown to improve the correlation between the occupancy of tyrosine-choline cation-pi interactions obtained from molecular dynamics simulations of a bilayer-bound bacterial phospholipase and experimental affinity data of the wild-type protein and selected mutants

Identification of a novel transport system in Borrelia burgdorferi that links the inner and outer membranes

Borrelia burgdorferi, the spirochete that causes Lyme disease, is a diderm organism that is similar to Gram-negative organisms in that it contains both an inner and outer membrane. Unlike typical Gram-negative organisms, however, B. burgdorferi lacks lipopolysaccharide (LPS). Using computational genome analyses and structural modeling, we identified a transport system containing six proteins in B. burgdorferi that are all orthologs to proteins found in the lipopolysaccharide transport (LPT) system that links the inner and outer membranes of Gram-negative organisms and is responsible for placing LPS on the surface of these organisms. While B. burgdorferi does not contain LPS, it does encode over 100 different surface-exposed lipoproteins and several major glycolipids, which like LPS are also highly amphiphilic molecules, though no system to transport these molecules to the borrelial surface is known. Accordingly, experiments supplemented by molecular modeling were undertaken to determine whether the orthologous LPT system identified in B. burgdorferi could transport lipoproteins and/or glycolipids to the borrelial outer membrane. Our combined observations strongly suggest that the LPT transport system does not transport lipoproteins to the surface. Molecular dynamic modeling, however, suggests that the borrelial LPT system could transport borrelial glycolipids to the outer membrane

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

New CHARMM force field parameters for dehydrated amino acid residues, the key to lantibiotic molecular dynamics simulations

Lantibiotics are an important class of naturally occurring antimicrobial peptides containing unusual dehydrated amino acid residues. In order to enable molecular dynamics simulations of lantibiotics, we have developed empirical force field parameters for dehydroalanine and dehydrobutyrine, which are compatible with the CHARMM all-atom force field. The parameters reproduce the geometries and energy barriers from MP2/6-31G*//MP2/cc-pVTZ quantum chemistry calculations. Experimental, predicted and calculated NMR chemical shifts for the amino protons and alpha-, beta- and carbonyl carbon atoms of the dehydrated residues are consistent with a significant charge redistribution. The new parameters are used to perform the first molecular dynamics simulations of nisin, a widely used but poorly understood lantibiotic, in an aqueous environment and in a phospholipid bilayer. The simulations show surface association of the peptide with membranes in agreement with solid state NMR data and formation of beta-turns in agreement with solution NMR

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

Unusual Sequence Effects on Nucleotide Excision Repair of Arylamine Lesions: DNA Bending/Distortion as a Primary Recognition Factor

The environmental arylamine mutagens are implicated in the etiology of various sporadic human cancers. Arylamine-modified dG lesions were studied in two fully paired 11-mer duplexes with a -G*C N- sequence context, in which G* is a C8-substituted dG adduct derived from fluorinated analogs of 4-aminobiphenyl (FABP), 2-aminofluorene (FAF) or 2-acetylaminofluorene (FAAF), and N is either dA or dT. The FABP and FAF lesions exist in a simple mixture of ‘stacked’ (S) and ‘B-type’ (B) conformers, whereas the N-acetylated FAAF also samples a ‘wedge’ (W) conformer. FAAF is repaired three to four times more efficiently than FABP and FAF. A simple A- to -T polarity swap in the G*C A/G*CT transition produced a dramatic increase in syn-conformation and resulted in 2- to 3-fold lower nucleotide excision repair (NER) efficiencies in Escherichia coli. These results indicate that lesion-induced DNA bending/thermodynamic destabilization is an important DNA damage recognition factor, more so than the local S/B-conformational heterogeneity that was observed previously for FAF and FAAF in certain sequence contexts. This work represents a novel 3\u27-next flanking sequence effect as a unique NER factor for bulky arylamine lesions in E. coli