A tree-based method for the rapid screening of chemical fingerprints

Background  

The fingerprint of a molecule is a bitstring based on its structure, constructed such that structurally similar molecules will have similar fingerprints. Molecular fingerprints can be used in an initial phase of drug development for identifying novel drug candidates by screening large databases for molecules with fingerprints similar to a query fingerprint.     

Spatial regulation and the rate of signal transduction activation

Of the many important signaling events that take place on the surface of a mammalian cell, activation of signal transduction pathways via interactions of cell surface receptors is one of the most important. Evidence suggests that cell surface proteins are not as freely diffusible as implied by the classic fluid mosaic model and that their confinement to membrane domains is regulated. It is unknown whether these dynamic localization mechanisms function to enhance signal transduction activation rate or to minimize cross talk among pathways that share common intermediates. To determine which of these two possibilities is more likely, we derive an explicit equation for the rate at which cell surface membrane proteins interact based on a Brownian motion model in the presence of endocytosis and exocytosis. We find that in the absence of any diffusion constraints, cell surface protein interaction rate is extremely high relative to cytoplasmic protein interaction rate even in a large mammalian cell with a receptor abundance of a mere two hundred molecules. Since a larger number of downstream signaling events needs to take place, each occurring at a much slower rate than the initial activation via association of cell surface proteins, we conclude that the role of co-localization is most likely that of cross-talk reduction rather than coupling efficiency enhancement.     

Recrafting the neighbor-joining method

Background  

The neighbor-joining method by Saitou and Nei is a widely used method for constructing phylogenetic trees. The formulation of the method gives rise to a canonical Θ(n ³) algorithm upon which all existing implementations are based.     

Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

Background  

The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class.     

Protein decoy assembly using short fragments under geometric constraints

A small set of protein fragments can represent adequately all known local protein structure. This set of fragments, along with a construction scheme that assembles these fragments into structures, defines a discrete (relatively small) conformation space, which approximates protein structures accurately. We generate protein decoys by sampling geometrically valid structures from this conformation space, biased by the secondary structure prediction for the protein. Unlike other methods, secondary structure prediction is the only protein-specific information used for generating the decoys. Nevertheless, these decoys are qualitatively similar to those found by others. The method works well for all-alpha proteins, and shows promising results for alpha and beta proteins.     

Characterization of the genomic structure of the mouse limbic system-associated membrane protein (Lsamp) gene

The Lsamp gene encodes the limbic system-associated membrane protein (LAMP) an immunoglobulin (Ig) superfamily member with three Ig domains and a glycosylphosphatidylinositol anchor. LAMP is expressed by neurons composing the limbic system, is highly conserved between rodents and human, and has structural and functional properties that substantiate its role in the formation of limbic circuits. We report here the genomic organization of the Lsamp gene. The Lsamp gene is composed of 11 exons distributed over 2.2 megabases (Mb). Two exons 1 are separated by approximately 1.6 Mb and contribute to the unusual large size of the gene. Alternative spliced Lsamp mRNAs are generated from distinct promoter regions associated with the two exons 1 that encode distinct signal peptides and thus generate identical native mature polypetides. Additional diversity is created by the use of two small exons to include an insertion of 23 amino acids within the polypeptide C-terminal region of the mature protein. The genomic features of the Lsamp gene described here indicate an intricate mechanism of gene expression regulation that may be relevant in the context of human neuropsychiatric and neurological disorders, where LAMP expression may be altered.