Pokefind: a novel topological filter for use with protein structure prediction

Motivation: Our focus has been on detecting topological properties that are rare in real proteins, but occur more frequently in models generated by protein structure prediction methods such as Rosetta. We previously created the Knotfind algorithm, successfully decreasing the frequency of knotted Rosetta models during CASP6. We observed an additional class of knot-like loops that appeared to be equally un-protein-like and yet do not contain a mathematical knot. These topological features are commonly referred to as slip-knots and are caused by the same mechanisms that result in knotted models. Slip-knots are undetectable by the original Knotfind algorithm. We have generalized our algorithm to detect them, and analyzed CASP6 models built using the Rosetta loop modeling method

GULP: Capabilities and prospects

The current status and capabilities of the atomistic simulation code GULP are described. In particular, the differences between versions 1.3.2 and 3.0 are detailed, as well as a concise pointer to applications in computational crystallography

Morphological Control of Ca3Al2(OH)12

The effect of a range of inorganic and organic crystal growth modifiers on the morphology of Ca3Al2(OH)12 has been studied. It has been found that some additives show a strong preference for a single crystal face forming polyhedral crystals whilst others are less selective, producing crystals with a less well defined morphology. In this way sulphite and dithionite preferentially interact with the {111} face producing octahedral crystals and nitrilotriacetic acid stabilises the {110} face forming rhombic dodecahedral crystals. Phosphate, however, leads to the formation of small needle-like crystals and the organic acids, N(CH2CO2H)2(CH2PO3H2), N(CH2CO2H)(CH2PO3H2)2, HN(CH2PO3H2)2, and H3CN(CH2PO3H2)2, produce near spherical crystals

Structure, Energetics, and Dynamics of Screw Dislocations in Even n-Alkane Crystals

Spiral hillocks on n-alkane crystal surfaces were observed immediately after Frank recognized the importance of screw dislocations for crystal growth, yet their structures and energies in molecular crystals remain ill-defined. To illustrate the structural chemistry of screw dislocations that are responsible for plasticity in organic crystals and upon which the organic electronics and pharmaceutical industries depend, molecular dynamics was used to examine heterochiral dislocation pairs with Burgers vectors along [001] in n-hexane, n-octane, and n-decane crystals. The cores were anisotropic and elongated in the (110) slip plane, with significant local changes in molecular position, orientation, conformation, and energy. This detailed atomic level picture produced a distribution of strain consistent with linear elastic theory, giving confidence in the simulations. Dislocations with doubled Burgers vectors split into pairs with elementary displacements. These results suggest a pathway to understanding the mechanical properties and failure associated with elastic and plastic deformation in soft crystals

The role of phosphonate speciation on the inhibition of barium sulfate precipitation

The inhibition of barium sulfate precipitation in the presence of phosphonate containing molecules was investigated experimentally and speciation curves were used to elucidate the interactions involved. Inhibition of precipitation was found to be pH dependent and loss of inhibition was observed at both very high and low pHs. Maximum inhibition for all the inhibitor molecules occurred at pH 8. While speciation curves showed that inhibition could be improved by the presence of 2 or more fully de-protonated phosphonate groups (for pure aminophosphonates) on the molecule at pH 8, at pH 12 inhibition was insensitive to the number of de- protonated phosphonate groups. It is, therefore, suggested that surface charge repulsion affects inhibition at very high pH. For molecules which are not pure aminophosphonates, stereochemistry as well as functional groups and their ionisation state appear to play a significant role in inhibition at 3<pH8

Dislocation-Actuated Growth and Inhibition of Hexagonal L-Cystine Crystallization at the Molecular Level

Crystallization of L-cystine is a critical process in the pathogenesis of kidney stone formation in cystinuria, a disorder affecting more than 20 000 individuals in the United States alone. In an effort to elucidate the crystallization of L-cystine and the mode of action of tailored growth inhibitors that may constitute effective therapies, real-time in situ atomic force microscopy has been used to investigate the surface micromorphology and growth kinetics of the {0001} faces of L-cystine at various supersaturations and concentrations of the growth inhibitor L-cystine dimethylester (CDME). Crystal growth is actuated by screw dislocations on the {0001} L-cystine surface, producing hexagonal spiral hillocks that are a consequence of six interlacing spirals of anisotropic molecular layers. The high level of elastic stress in the immediate vicinity around the dislocation line results in a decrease in the step velocities and a corresponding increase in the spacing of steps. The kinetic curves acquired in the presence of CDME conform to the classical Cabrera–Vermilyea model. Anomalous birefringence in the {101̅0} growth sectors, combined with computational modeling, supports a high fidelity of stereospecific binding of CDME, in a unique orientation, exclusively at one of the six crystallographically unique projections on the {1010} plane

Timoshenko Bending and Eshelby Twisting Predicted in Molecular Nanocrystals

Well-formed crystals are polyhedral with flat facets and sharp edges. Nevertheless, a remarkable number of molecular crystals can bend and twist during growth. Many others can be distorted by applying external forces or creating heterogeneities by temperature gradient or photochemical reaction. As part of an effort to identify the forces that so commonly deform molecular crystals and to characterize their consequences, a force field is evaluated for its ability to predict mechanical distortions in nanocrystals. Macroscopic materials provide estimates of the expected responses that were tested here in silico for "molecular bimetallic strips" created from rods of iodoform and bromoform in smooth contact and nanocrystalline rods of iodoform with left and right screw dislocations. It was demonstrated that an optimized force field based largely on AMBER parameters matches expectations for elastic and plastic distortions, despite the fact that these mechanical responses are far removed from the force field parametrization set

Definition, conservation and epigenetics of housekeeping and tissue-enriched genes

<p>Abstract</p> <p>Background</p> <p>Housekeeping genes (HKG) are constitutively expressed in all tissues while tissue-enriched genes (TEG) are expressed at a much higher level in a single tissue type than in others. HKGs serve as valuable experimental controls in gene and protein expression experiments, while TEGs tend to represent distinct physiological processes and are frequently candidates for biomarkers or drug targets. The genomic features of these two groups of genes expressed in opposing patterns may shed light on the mechanisms by which cells maintain basic and tissue-specific functions.</p> <p>Results</p> <p>Here, we generate gene expression profiles of 42 normal human tissues on custom high-density microarrays to systematically identify 1,522 HKGs and 975 TEGs and compile a small subset of 20 housekeeping genes which are highly expressed in all tissues with lower variance than many commonly used HKGs. Cross-species comparison shows that both the functions and expression patterns of HKGs are conserved. TEGs are enriched with respect to both segmental duplication and copy number variation, while no such enrichment is observed for HKGs, suggesting the high expression of HKGs are not due to high copy numbers. Analysis of genomic and epigenetic features of HKGs and TEGs reveals that the high expression of HKGs across different tissues is associated with decreased nucleosome occupancy at the transcription start site as indicated by enhanced DNase hypersensitivity. Additionally, we systematically and quantitatively demonstrated that the CpG islands' enrichment in HKGs transcription start sites (TSS) and their depletion in TEGs TSS. Histone methylation patterns differ significantly between HKGs and TEGs, suggesting that methylation contributes to the differential expression patterns as well.</p> <p>Conclusion</p> <p>We have compiled a set of high quality HKGs that should provide higher and more consistent expression when used as references in laboratory experiments than currently used HKGs. The comparison of genomic features between HKGs and TEGs shows that HKGs are more conserved than TEGs in terms of functions, expression pattern and polymorphisms. In addition, our results identify chromatin structure and epigenetic features of HKGs and TEGs that are likely to play an important role in regulating their strikingly different expression patterns.</p

Experimental library screening demonstrates the successful application of computational protein design to large structural ensembles

The stability, activity, and solubility of a protein sequence are determined by a delicate balance of molecular interactions in a variety of conformational states. Even so, most computational protein design methods model sequences in the context of a single native conformation. Simulations that model the native state as an ensemble have been mostly neglected due to the lack of sufficiently powerful optimization algorithms for multistate design. Here, we have applied our multistate design algorithm to study the potential utility of various forms of input structural data for design. To facilitate a more thorough analysis, we developed new methods for the design and high-throughput stability determination of combinatorial mutation libraries based on protein design calculations. The application of these methods to the core design of a small model system produced many variants with improved thermodynamic stability and showed that multistate design methods can be readily applied to large structural ensembles. We found that exhaustive screening of our designed libraries helped to clarify several sources of simulation error that would have otherwise been difficult to ascertain. Interestingly, the lack of correlation between our simulated and experimentally measured stability values shows clearly that a design procedure need not reproduce experimental data exactly to achieve success. This surprising result suggests potentially fruitful directions for the improvement of computational protein design technology

Mapping the genetic architecture of gene expression in human liver

Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process. © 2008 Schadt et al