Browsing by Author "Fernandez, Ariel"
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Item Molecular basis of gene dosage sensitivity(2009) Chen, Jianping; Fernandez, ArielDeviation of gene expression from normal levels has been associated with diseases. Both under- and overexpression of genes could lead to deleterious biological consequences. Dosage balance has been proposed to be a key issue of determining gene expression phenotype. Gene deletion or overexpression of any component in a protein complex produces abnormal phenotypes. As a result, interacting partners should be co-expressed to avoid dosage imbalance effects. The strength of transcriptional co-regulation of interacting partners is supposed to reflect gene dosage sensitivity. Although many cases of dosage imbalance effects have been reported, the molecular attributes determining dosage sensitivity remain unknown. This thesis uses a protein structure analysis protocol to explore the molecular basis of gene dosage sensitivity, and studies the post-transcriptional regulation of dosage sensitive genes. Solvent-exposed backbone hydrogen bond (SEBH or called as dehydron) provides a structure marker for protein interaction. Protein structure vulnerability, defined as the ratio of SEBHs to the overall number of backbone hydrogen bonds, quantifies the extent to which protein relies on its binding partners to maintain structure integrity. Genes encoding vulnerable proteins need to be highly co-expressed with their interacting partners. Protein structure vulnerability may hence serves as a structure marker for dosage sensitivity. This hypothesis is examined through the integration of gene expression, protein structure and interaction data sets. Both gene co-expression and protein structure vulnerability are calculated for each interacting subunits from human and yeast complexes. It turns out that structure vulnerability quantifies dosage sensitivity for both temporal phases (yeast) and tissue-specific (human) patterns of mRNA expression, determining the extent of co-expression similarity of binding partners. Highly dosage sensitive genes encode proteins which are vulnerable to water attack. They are subject to tight post-transcriptional regulation. In human, this extra regulation is achieved through extensive microRNA targeting of genes coding for extremely vulnerable proteins. In yeast, on the other hand, our results imply that such a regulation is likely achieved through sequestration of the extremely vulnerable proteins into aggregated states. The 85 genes encoding extremely vulnerable proteins contain the five confirmed yeast prions. It has been proposed that yeast prion protein aggregation could produce multiple phenotypes important for cell survival in some particular circumstances. These results suggest that extremely vulnerable proteins resorting to aggregation to buffer the deleterious consequences of dosage imbalance. However, a rigorous proof will require a structure-based integration of information drawn from the interactome, transcriptome and post-transcriptional regulome.Item Protein wrapping and protein hydration(2008) Chen, Jianping; Fernandez, ArielHydrogen bond plays an important role in stability, dynamics and function of protein. Most of backbone hydrogen bonds are well wrapped by nonpolar groups of side chains. However, there are a small portion of hydrogen bonds vulnerable to water attack. Those under-wrapped hydrogen bonds, termed as "dehydron", are sensitive to the change in the local electrostatic environment. Dehydrons constitute a hot spot for protein interactions. They have been identified as structural marker for protein association, proteamic connectivity and protein-ligand binding. The effects of dehydrons on protein hydration shell are assessed by studying the mobility of hydration water. Calculation of water residence times of all residues reveals that dehydrons enhance the water mobility and promote the most intense loosening of hydration shell. Targeting loose hydration shells induced by dehydrons provides a powerful strategy in rational drug design.Item Specificity in the druggable kinome: Molecular basis and its applications(2009) Zhang, Xi; Fernandez, ArielRational design of kinase inhibitors remains a challenge partly because there is no clear delineation of the molecular features that direct the pharmacological impact towards clinically relevant targets. In this thesis, we focus on a structural marker and construct a kinase classifier that enables the accurate prediction of pharmacological differences. Our indicator is a microenvironmental descriptor that quantifies the propensity for water exclusion around preformed polar pairs. The results suggest that targeting polar dehydration patterns heralds a new generation of drugs that enable a tighter control of specificity than designs aimed at promoting ligand-kinase pairwise interactions. As an application of the structural marker, we introduce a computational screening approach which provides a tool for extensive screening that uses experimentally obtained small-scale profiles as input data and makes predictions for a larger kinase set. These predictions result from a propagation of the reduced profile, exploiting a structural comparison of kinases based on a feature-similarity matrix. The comparison focuses on a molecular marker for specificity and promiscuity of kinase inhibitors. Our approach enables the computational high-throughput screening of entire libraries of compounds to search for suitable leads, mapping their inhibitory impact on a sizable sample of the human kinome. Yet another application of the structural marker is advocated by illustrating its cleaning efficacy. In this regard, we reassess the possibility to turn multi-target drugs into real clinical opportunities through judicious redesign. A general cleaning strategy, which adopts the structural marker as redesigning instruction, is proposed and exemplified by a workable approach.