Sampling of conformational ensemble for virtual screening using molecular dynamics simulations and normal mode analysis

Aim: Molecular dynamics simulations and normal mode analysis are well-established approaches to generate receptor conformational ensembles (RCEs) for ligand docking and virtual screening. Here, we report new fast molecular dynamics-based and normal mode analysis-based protocols combined with conformational pocket classifications to efficiently generate RCEs. Materials \& methods: We assessed our protocols on two well-characterized protein targets showing local active site flexibility, dihydrofolate reductase and large collective movements, CDK2. The performance of the RCEs was validated by distinguishing known ligands of dihydrofolate reductase and CDK2 among a dataset of diverse chemical decoys. Results \& discussion: Our results show that different simulation protocols can be efficient for generation of RCEs depending on different kind of protein flexibility

Radio signatures of solar energetic particles during the 23rd solar cycle

We present the association rates between solar energetic particles (SEPs) and the radio emission signatures in the corona and IP space during the entire solar cycle 23. We selected SEPs associated with X and M-class flares from the visible solar hemisphere. All SEP events are also accompanied by coronal mass ejections. Here, we focus on the correlation between the SEP events and the appearance of radio type II, III and IV bursts on dynamic spectra. For this we used the available radio data from ground-based stations and the Wind/WAVES spacecraft. The associations are presented separately for SEP events accompanying activity in the eastern and western solar hemisphere. We find the highest association rate of SEP events to be with type III bursts, followed by types II and IV. Whereas for types III and IV no longitudinal dependence is noticed, these is a tendency for a higher SEP-association rate with type II bursts in the eastern hemisphere. A comparison with reports from previous studies is briefly discussed.Comment: http://adsabs.harvard.edu.ezproxy.obspm.fr/abs/2013CEAB...37..541

On the Unitarity of D=9,10,11 Conformal Supersymmetry

We consider the unitarity of D=9,10,11 conformal supersymmetry using the recently established classification of the UIRs of the superalgebras osp(1|2n,R).Comment: 7 pages, LATEX2e{czjphys} (amsmath,amssymb); v3: important corrections, Plenary talk by VKD at the XIII Colloquium "Quantum Groups and Integrable Systems", Prague, 17-19.6.2004; to appear in Czech. J. Phys.; v4: small corrections to coincide with journal versio

PCE: web tools to compute protein continuum electrostatics

PCE (protein continuum electrostatics) is an online service for protein electrostatic computations presently based on the MEAD (macroscopic electrostatics with atomic detail) package initially developed by D. Bashford [(2004) Front Biosci., 9, 1082–1099]. This computer method uses a macroscopic electrostatic model for the calculation of protein electrostatic properties, such as pK(a) values of titratable groups and electrostatic potentials. The MEAD package generates electrostatic energies via finite difference solution to the Poisson–Boltzmann equation. Users submit a PDB file and PCE returns potentials and pK(a) values as well as color (static or animated) figures displaying electrostatic potentials mapped on the molecular surface. This service is intended to facilitate electrostatics analyses of proteins and thereby broaden the accessibility to continuum electrostatics to the biological community. PCE can be accessed at

Analyzing Effects of Naturally Occurring Missense Mutations

Single-point mutation in genome, for example, single-nucleotide polymorphism (SNP) or rare genetic mutation, is the change of a single nucleotide for another in the genome sequence. Some of them will produce an amino acid substitution in the corresponding protein sequence (missense mutations); others will not. This paper focuses on genetic mutations resulting in a change in the amino acid sequence of the corresponding protein and how to assess their effects on protein wild-type characteristics. The existing methods and approaches for predicting the effects of mutation on protein stability, structure, and dynamics are outlined and discussed with respect to their underlying principles. Available resources, either as stand-alone applications or webservers, are pointed out as well. It is emphasized that understanding the molecular mechanisms behind these effects due to these missense mutations is of critical importance for detecting disease-causing mutations. The paper provides several examples of the application of 3D structure-based methods to model the effects of protein stability and protein-protein interactions caused by missense mutations as well

DG-AMMOS: A New tool to generate 3D conformation of small molecules using Distance Geometry and Automated Molecular Mechanics Optimization for in silico Screening

<p>Abstract</p> <p>Background</p> <p>Discovery of new bioactive molecules that could enter drug discovery programs or that could serve as chemical probes is a very complex and costly endeavor. Structure-based and ligand-based <it>in silico </it>screening approaches are nowadays extensively used to complement experimental screening approaches in order to increase the effectiveness of the process and facilitating the screening of thousands or millions of small molecules against a biomolecular target. Both <it>in silico </it>screening methods require as input a suitable chemical compound collection and most often the 3D structure of the small molecules has to be generated since compounds are usually delivered in 1D SMILES, CANSMILES or in 2D SDF formats.</p> <p>Results</p> <p>Here, we describe the new open source program DG-AMMOS which allows the generation of the 3D conformation of small molecules using Distance Geometry and their energy minimization via Automated Molecular Mechanics Optimization. The program is validated on the Astex dataset, the ChemBridge Diversity database and on a number of small molecules with known crystal structures extracted from the Cambridge Structural Database. A comparison with the free program Balloon and the well-known commercial program Omega generating the 3D of small molecules is carried out. The results show that the new free program DG-AMMOS is a very efficient 3D structure generator engine.</p> <p>Conclusion</p> <p>DG-AMMOS provides fast, automated and reliable access to the generation of 3D conformation of small molecules and facilitates the preparation of a compound collection prior to high-throughput virtual screening computations. The validation of DG-AMMOS on several different datasets proves that generated structures are generally of equal quality or sometimes better than structures obtained by other tested methods.</p

MS-DOCK: Accurate multiple conformation generator and rigid docking protocol for multi-step virtual ligand screening

<p>Abstract</p> <p>Background</p> <p>The number of protein targets with a known or predicted tri-dimensional structure and of drug-like chemical compounds is growing rapidly and so is the need for new therapeutic compounds or chemical probes. Performing flexible structure-based virtual screening computations on thousands of targets with millions of molecules is intractable to most laboratories nor indeed desirable. Since shape complementarity is of primary importance for most protein-ligand interactions, we have developed a tool/protocol based on rigid-body docking to select compounds that fit well into binding sites.</p> <p>Results</p> <p>Here we present an efficient multiple conformation rigid-body docking approach, MS-DOCK, which is based on the program DOCK. This approach can be used as the first step of a multi-stage docking/scoring protocol. First, we developed and validated the Multiconf-DOCK tool that generates several conformers per input ligand. Then, each generated conformer (bioactives and 37970 decoys) was docked rigidly using DOCK6 with our optimized protocol into seven different receptor-binding sites. MS-DOCK was able to significantly reduce the size of the initial input library for all seven targets, thereby facilitating subsequent more CPU demanding flexible docking procedures.</p> <p>Conclusion</p> <p>MS-DOCK can be easily used for the generation of multi-conformer libraries and for shape-based filtering within a multi-step structure-based screening protocol in order to shorten computation times.</p

AMMOS: A Software Platform to Assist in silico Screening

Three software packages based on the common platform of AMMOS (Automated Molecular Mechanics Optimization tool for in silico Screening) for assisting virtual ligand screening purposes have been recently developed. DG-AMMOS allows generation of 3D conformations of small molecules using distance geometry and molecular mechanics optimization. AMMOS_SmallMol is a package for structural refinement of compound collections that can be used prior to docking experiments. AMMOS_ProtLig is a package for energy minimization of protein-ligand complexes. It performs an automatic procedure for molecular mechanics minimization at different levels of flexibility - from rigid to fully flexible structures of both the ligand and the receptor. The packages have been tested on small molecules with a high structural diversity and proteins binding sites of completely different geometries and physicochemical properties. The platform is developed as an open source software and can be used in a broad range of in silico drug design studies