Juan J. Perez

Molecular Polarization Potential Maps of the Nucleic Acid Bases

Ab initio calculations at the SCF level were carried out to compute the polarization potential map NM of the nucleic acid bases: cytosine, thymine, uracil, adedine, and guanine. For this purpose, the Dunning`s 9s5p basis set contracted to a split-valence, was selected to perform the calculations. The molecular polarization potential (MPP) at each point was evaluated by the difference between the interaction energy of the molecule with a unit point charge and the molecular electrostatic potential (MEP) at that point. MEPS and MPPS for the different molecules were computed with a density of 5 points/{Angstrom}{sup 2} on the van der Waals surface of each molecule, defined using the van der Waals radii. Due to the symmetry of the molecules, only half the points were computed. The total number of points calculated was 558 for cytosine, 621 for thymine, 526 for uracil, 666 for adenine, and 699 for guanine. The results of these calculations are analyzed in terms of their implications on the molecular interactions between pairs of nucleic acid bases. 23 refs., 5 figs., 1 tab.

Effect of ions on a dipalmitoyl phosphatidylcholine bilayer. a molecular dynamics simulation study.

The effect of physiological concentrations of different chlorides on the structure of a dipalmitoyl phosphatidylcholine (DPPC) bilayer has been investigated through atomistic molecular dynamics simulations. These calculations provide support to the concept that Li+, Na+, Ca2+, Mg2+, Sr2+, Ba2+, and Ac3+, but not K+, bind to the lipid-head oxygens. Ion binding exhibits an influence on lipid order, area per lipid, orientation of the lipid head dipole, the charge distribution in the system, and therefore the electrostatic potential across the head-group region of the bilayer. These structural effects are sensitive to the specific characteristics of each cation, i.e., radius, charge, and coordination properties. These results provide evidence aimed at shedding some light into the apparent contradictions among different studies reported recently regarding the ordering effect of ions on zwitterionic phosphatidylcholine lipid bilayers.

Managing molecular diversity

The present work provides an overview of the different methods used in molecular diversity analysis. Issues like identifying voids in proprietary databases, reducing the number of redundancies present in databases, or designing focused libraries by grouping compounds similar to a template with the aim to fine tune its properties, are potent diversity analysis tools that may be used to optimize molecules based on their properties and specifically, to speed up the process of lead discovery and optimization. The present work describes first methods that are used to describe molecular systems. This is followed by a section devoted to describe different measures of similarity between molecules, to finish with a description of different methods used to select subsets molecules according to the constraints imposed. The final section deals with the validation of these methods, based on different studies available in the literature.

Differential binding mode of diverse cyclooxygenase inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective COX inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of COX available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different COX inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of COX inhibitors, and are expected to contribute to the design of new selective compounds.

Molecular Dynamics Simulations of Phospholipid Bilayers

Molecular dynamics (MD) simulations at 37 degrees C have been performed on three phospholipid bilayer systems composed of the lipids DLPE, DOPE, and DOPC. The model used included 24 explicit lipid molecules and explicit waters of solvation in the polar head group regions, together with constant-pressure periodic boundary conditions in three dimensions. Using this model, a MD simulation samples part of an infinite planar lipid bilayer. The lipid dynamics and packing behavior were characterized. Furthermore, using the results of the simulations, a number of diverse properties including bilayer structural parameters, hydrocarbon chain order parameters, dihedral conformations, electron density profile, hydration per lipid, and water distribution along the bilayer normal were calculated. Many of these properties are available for the three lipid systems chosen, making them well suited for evaluating the model and protocols used in these simulations by direct comparisons with experimental data. The calculated MD behavior, chain disorder, and lipid packing parameter, i.e. the ratio of the effective areas of hydrocarbon tails and head group per lipid (a(t)/ah), correctly predict the aggregation preferences of the three lipids observed experimentally at 37 degrees C, namely: a gel bilayer for DLPE, a hexagonal tube for DOPE, and a liquid crystalline bilayer for DOPC. In addition, the model and conditions used in the MD simulations led to good agreement of the calculated properties of the bilayers with available experimental results, demonstrating the reliability of the simulations. The effects of the cis unsaturation in the hydrocarbon chains of DOPE and DOPC, compared to the fully saturated one in DLPE, as well as the effects of the different polar head groups of PC and PE with the same unsaturated chains on the lipid packing and bilayer structure have been investigated. The results of these studies indicate the ability of MD methods to provide molecular-level insights into the structure and dynamics of lipid assemblies.

Structural Rearrangements of Rhodopsin Subunits in a Dimer Complex: a Molecular Dynamics Simulation Study

Abstract The present work reports a 0.1 μs molecular dynamics simulation of a bovine rhodopsin dimer based on a recently reported semi-empirical model obtained by fitting two monomers from the crystal structure to atomic force microscopy maps (Fotiadis et al. Curr Opin Struct Biol 16, 252, 2006). The simulation shows that the quaternary arrangement is stable although subtle rearrangements in its tertiary elements are observed during the first 60 ns of the trajectory. The comparison with a parallel 0.1 μs simulation of a single monomer in the same conditions and using the same protocol allows the study of subunit-subunit interactions on the dimer interface together with the structural effects associated to the dimer formation. The present study describes the interface of a TM4/TM5-TM4/TM5 dimer at an atomistic level including an analysis of the energy contributions to the interaction of each part of the protein involved. We also compare the differences in the structure of the single monomer with those of the dimer subunits with the aim of understanding the changes required for the dimer formation.

Randomized tree construction algorithm to explore energy landscapes

In this work, a new method for exploring conformational energy landscapes is described. The method, called transition‐rapidly exploring random tree (T‐RRT), combines ideas from statistical physics and robot path planning algorithms. A search tree is constructed on the conformational space starting from a given state. The tree expansion is driven by a double strategy: on the one hand, it is naturally biased toward yet unexplored regions of the space; on the other, a Monte Carlo‐like transition test guides the expansion toward energetically favorable regions. The balance between these two strategies is automatically achieved due to a self‐tuning mechanism. The method is able to efficiently find both energy minima and transition paths between them. As a proof of concept, the method is applied to two academic benchmarks and the alanine dipeptide.

Effect of Force Field Parameters on Sodium and Potassium Ion Binding to Dipalmitoyl Phosphatidylcholine Bilayers.

The behavior of electrolytes in molecular dynamics simulations of zwitterionic phospholipid bilayers is very sensitive to the force field parameters used. Here, several 200 ns molecular dynamics of simulations of dipalmitoyl phosphotidylcholine (PC) bilayers in 0.2 M sodium or potassium chloride using various common force field parameters for the cations are presented. All employed parameter sets give a larger number of Na(+) ions than K(+) ions that bind to the lipid heads, but depending on the parameter choice quite different results are seen. A wide range of coordination numbers for the Na(+) and K(+) ions is also observed. These findings have been analyzed and compared to published experimental data. Some simulations produce aggregates of potassium chloride, indicating (in accordance with published simulations) that these force fields do not reproduce the delicate balance between salt and solvated ions. The differences between the force fields can be characterized by one single parameter, the electrostatic radius of the ion, which is correlated to σMO (M represents Na(+)/K(+)), the Lennard-Jones radius. When this parameter exceeds a certain threshold, binding to the lipid heads is no longer observed. One would, however, need more accurate experimental data to judge or rank the different force fields precisely. Still, reasons for the poor performance of some of the parameter sets are clearly demonstrated, and a quality control procedure is provided.

Iodine Atoms: A New Molecular Feature for the Design of Potent Transthyretin Fibrillogenesis Inhibitors

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis.

Structural basis of the dynamic mechanism of ligand binding to cyclooxygenase.

Molecular modeling studies performed on the two cyclooxygenase (COX) isozymes suggest that the cavity at the mouth of the active site on the membrane domain that may act as an actual binding site of COX ligands. Actual docking of different inhibitors at this site provides a structural basis to explain the dynamics of COX inhibition.