The next-generation sequencing technologies, among them exome sequencing, have now brought the dream of individual genome identification close to reality. However, new advances in genome sequencing are necessary but not sufficient for identifying functionally important variants and understanding the origins of many diseases. Specific human phenotype is largely determined by stability, activity, and interactions between numerous biomolecules which work together to provide specific cellular functions. Although the majority of genetic variations are likely to be neutral, a substantial fraction of them might explain the origins of Mendelian and complex diseases. Somatic mutations may contribute significantly to tumorigenesis, and driver mutations may allow cancer cells to sustain proliferative signaling. However, finding functionally important mutations and predicting their molecular mechanisms largely remains an unsolved problem. If a disease is caused by a malfunction of a particular protein, the effects caused by missense mutations can be pinpointed by in silico modeling and it makes it more feasible to find a treatment that will reverse the effect. Signaling networks involve a dense network of protein interactions and at the same time are often deregulated in many diseases including cancer. Therefore the analysis of protein complexes, disease-related interaction networks and the effect of disease mutations on network properties would give us important clues for understanding the molecular mechanisms of diseases and allow their treatment and prevention. In fact many disease mutations are located on protein binding interfaces and may affect the specificity of recognition and protein binding affinity. There are different ways to modulate in a cell the nature and strength of protein-protein interactions and thereby regulate protein binding and coordinate functions of different pathways. Reversible phosphorylation is one of the important regulatory mechanisms;it may cause protein conformational changes and affect the binding affinity or specificity of interactions. Moreover there are many known disease missense mutations which disrupt and alter the phosphorylation patterns.

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Budget End
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1
Fiscal Year
2013
Total Cost
$1,115,664
Indirect Cost
Name
National Library of Medicine
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Type
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Goncearenco, Alexander; Li, Minghui; Simonetti, Franco L et al. (2017) Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows. Methods Mol Biol 1647:221-236
El Kennani, Sara; Adrait, Annie; Shaytan, Alexey K et al. (2017) MS_HistoneDB, a manually curated resource for proteomic analysis of human and mouse histones. Epigenetics Chromatin 10:2
Li, Minghui; Goncearenco, Alexander; Panchenko, Anna R (2017) Annotating Mutational Effects on Proteins and Protein Interactions: Designing Novel and Revisiting Existing Protocols. Methods Mol Biol 1550:235-260
Rogozin, Igor B; Pavlov, Youri I; Goncearenco, Alexander et al. (2017) Mutational signatures and mutable motifs in cancer genomes. Brief Bioinform :
Goncearenco, Alexander; Rager, Stephanie L; Li, Minghui et al. (2017) Exploring background mutational processes to decipher cancer genetic heterogeneity. Nucleic Acids Res :
Rogozin, Igor B; Lada, Artem G; Goncearenco, Alexander et al. (2016) Activation induced deaminase mutational signature overlaps with CpG methylation sites in follicular lymphoma and other cancers. Sci Rep 6:38133
Draizen, Eli J; Shaytan, Alexey K; Mariño-Ramírez, Leonardo et al. (2016) HistoneDB 2.0: a histone database with variants--an integrated resource to explore histones and their variants. Database (Oxford) 2016:
Li, Minghui; Kales, Stephen C; Ma, Ke et al. (2016) Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation. Cancer Res 76:561-71
Shaytan, Alexey K; Armeev, Grigoriy A; Goncearenco, Alexander et al. (2016) Coupling between Histone Conformations and DNA Geometry in Nucleosomes on a Microsecond Timescale: Atomistic Insights into Nucleosome Functions. J Mol Biol 428:221-237
Shaytan, Alexey K; Armeev, Grigoriy A; Goncearenco, Alexander et al. (2016) Trajectories of microsecond molecular dynamics simulations of nucleosomes and nucleosome core particles. Data Brief 7:1678-81

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