Molecular dynamics simulations and drug discovery

This review discusses the many roles atomistic computer simulations of macromolecular (for example, protein) receptors and their associated small-molecule ligands can play in drug discovery, including the identification of cryptic or allosteric binding sites, the enhancement of traditional virtual-screening methodologies, and the direct prediction of small-molecule binding energies. The limitations of current simulation methodologies, including the high computational costs and approximations of molecular forces required, are also discussed. With constant improvements in both computer power and algorithm design, the future of computer-aided drug design is promising; molecular dynamics simulations are likely to play an increasingly important role

Free energies of binding of R- and S-propranolol to wild-type and F483A mutant cytochrome P450 2D6 from molecular dynamics simulations

Detailed molecular dynamics (MD) simulations have been performed to reproduce and rationalize the experimental finding that the F483A mutant of CYP2D6 has lower affinity for R-propranolol than for S-propranolol. Wild-type (WT) CYP2D6 does not show this stereospecificity. Four different approaches to calculate the free energy differences have been investigated and were compared to the experimental binding data. From the differences between calculations based on forward and backward processes and the closure of thermodynamic cycles, it was clear that not all simulations converged sufficiently. The approach that calculates the free energies of exchanging R-propranolol with S-propranolol in the F483A mutant relative to the exchange free energy in WT CYP2D6 accurately reproduced the experimental binding data. Careful inspection of the end-points of the MD simulations involved in this approach, allowed for a molecular interpretation of the observed differences

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Molecular dynamics simulations of K+ -Cl- ion pair in polar mixtures of acetone and water: Preferential solvation and structural studies

Molecular dynamics simulation studies have been performed for a series of polar mixtures of acetone and water containing a K+ -Cl- ion pair. We have obtained the potentials of mean force (PMFs) for 15 mixtures spanning the whole composition range from 0% to 100% acetone. The PMFs indicate the presence of a stable contact ion pair (CIP), a solvent assisted ion pair (SAIP) and a solvent separated ion pair (SSIP) in all the compositions with acetone mole fraction (X-acetone) 0.50 and X-acetone 0.90, PMFs show the existence of only a stable CIP. While the stability of CIPs in mixtures increases with xamtone, the reverse trend is observed for SAIPs. The determination of thermodynamic properties suggests that entropy favours the CIPs and SAIPs in all the mixtures. The analysis of radial distribution functions using Kirkwood-Buff (KB) integrals explains the preferential solvation of the ion pair. We observed that in all the mixtures, K+ -Cl- ion pair is preferentially solvated by water. Running coordination numbers of solvent molecules around the ion pair and preferential binding parameters also support the above observations. The dynamical aspects have been explored by calculating self -diffusion constants and hydrogen bond dynamics. (C) 2015 Elsevier B.V. All rights reserved

Thermodynamics of association of water soluble fullerene derivatives [, n=0, 2, 4, 8 and 12] in aqueous media

The thermodynamics of association of fullerene [] and water-soluble fullerene derivatives, i.e., fullerols [, where, n = 2, 4, 8, 12] in aqueous solutions have been studied using molecular dynamics simulations. The potentials of mean force (PMFs) bring out the tendency of aggregation of these nanostructures in water. The extent of hydroxylation seems to have a minor effect on the depth of the contact minima (the first minimum in the PMFs). The positions of the subsequent minima and maxima in the PMFs change with the size of the solute molecules. Higher stability of the contact state of highly hydroxylated fullerols is due to the van der Waals interactions whereas intermolecular solute-solvent hydrogen bonding nearly flattens the PMFs beyond the minima for higher fullerols. The solvent contributions to the PMFs for all the solute particles studied here are positive. Entropic and enthalpic contributions to the association of solute molecules are calculated in the isothermal-isobaric (NPT) ensemble. We find that the contact pair formation is governed by entropy with the enthalpic contributions being highly unfavorable, whereas the solvent assisted and solvent separated configurations show entropy-enthalpy compensation. Synopsis: Aqueous solutions of fullerene have found applications in molecular sensing devices, biochemistry and environmental science. Therefore, it is necessary to have a microscopic understanding of the solvation structure of such macromolecules. Association and dynamics of fullerene and fullerols [] in water are addressed by molecular dynamics simulations

The pervasive solvent-separated sodium chloride ion pair in water-DMSO mixtures

Sodium chloride exists as a contact ion pair (CIP) as well as a solvent-separated ion pair (SSIP) in its solutions in water and in dimethyl sulphoxide (DMSO). In a mixture of these two solvents, the CIP is not formed in the two mixture compositions with chi(DMSO) = 0.35 and 0.21 and the ions stay as the SSIP near an interionic distance of 5.0 Angstrom. This has been shown by constructing the ion-ion potentials of mean force and by following the ion-pair trajectories initiated at various initial ion-pair separations in the two solvent mixtures

Radial and orientational solvation structure of the sodium chloride ion pair in dimethyl sulfoxide

The structures of the solvation shells around each ion of the Na+-Cl- ion pair in liquid dimethyl sulfoxide (DMSO) have been studied in terms of the ion-solvent radial distribution functions (RDFs) and the ion-solvent orientational distribution functions (ODFs) at the three interionic separations of 2.6 Angstrom 4.9 Angstrom, and 7.2 Angstrom. The solvation shell around the sodium ion consists of only three DMSO molecules at the ion-ion separation of 2.6 W and this number grows to live DMSO molecules at interionic separation 4.9 K and beyond. These are in contrast with the octahedral solvation shells around sodium ion in water at all ion-ion separations, where the chloride ion replaces a molecule of water only at a short interionic distance of 2.7 A. The orientational structure of the solvent around the ion pair has been probed by dividing the DMSO solvent into five spatial regions and analyzing the angular distributions in each region. In the shell near the Naf ion, the orientation of the sulphur-oxygen vector in DMSO is sharply peaked about 155 degrees away from the sodium-sulphur vector for all the three interionic distances. Similarly, the orientation of the DMSO dipole vector is also sharply peaked about 155 degrees away from the sodium-DMSO center of mass (COM) vector. In the shell near the Cl- ion, the orientation of the sulphur-oxygen vector with respect to the chloride-sulphur vector shows broader peaks in the range 20 degrees-100 degrees. The solvent dipole vector gets oriented in a similar fashion with respect to the chloride-COM vector in this shell. In the regions far from the Na+ and Cl- solvation shells, both the sulphur-oxygen vector and the solvent dipole vector have broad distributions covering all the angles except the parallel and the antiparallel alignments. The angles between the Na+-S-O plane (or the Cl--S-O plane) and the S-Na+-C1(-) plane do not show a preference for any specific inclination, in any of the spatial regions around the ion pair. These broad distributions are indicative of a weaker second shell around the ion pair in DMSO than the second shell found in water and are a consequence of the near absence of hydrogen bonding in DMSO. (C) 199