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AlQuraishi, Mohammed

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AlQuraishi

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Mohammed

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AlQuraishi, Mohammed
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    An affinity-structure database of helix-turn-helix: DNA complexes with a universal coordinate system
    (BioMed Central, 2015) AlQuraishi, Mohammed; Tang, Shengdong; Xia, Xide
    Background: Molecular interactions between proteins and DNA molecules underlie many cellular processes, including transcriptional regulation, chromosome replication, and nucleosome positioning. Computational analyses of protein-DNA interactions rely on experimental data characterizing known protein-DNA interactions structurally and biochemically. While many databases exist that contain either structural or biochemical data, few integrate these two data sources in a unified fashion. Such integration is becoming increasingly critical with the rapid growth of structural and biochemical data, and the emergence of algorithms that rely on the synthesis of multiple data types to derive computational models of molecular interactions. Description We have developed an integrated affinity-structure database in which the experimental and quantitative DNA binding affinities of helix-turn-helix proteins are mapped onto the crystal structures of the corresponding protein-DNA complexes. This database provides access to: (i) protein-DNA structures, (ii) quantitative summaries of protein-DNA binding affinities using position weight matrices, and (iii) raw experimental data of protein-DNA binding instances. Critically, this database establishes a correspondence between experimental structural data and quantitative binding affinity data at the single basepair level. Furthermore, we present a novel alignment algorithm that structurally aligns the protein-DNA complexes in the database and creates a unified residue-level coordinate system for comparing the physico-chemical environments at the interface between complexes. Using this unified coordinate system, we compute the statistics of atomic interactions at the protein-DNA interface of helix-turn-helix proteins. We provide an interactive website for visualization, querying, and analyzing this database, and a downloadable version to facilitate programmatic analysis. Conclusions: This database will facilitate the analysis of protein-DNA interactions and the development of programmatic computational methods that capitalize on integration of structural and biochemical datasets. The database can be accessed at http://ProteinDNA.hms.harvard.edu.
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    A multiscale statistical mechanical framework integrates biophysical and genomic data to assemble cancer networks
    (2014) AlQuraishi, Mohammed; Koytiger, Grigoriy; Jenney, Anne; Macbeath, Gavin; Sorger, Peter
    Functional interpretation of genomic variation is critical to understanding human disease but it remains difficult to predict the effects of specific mutations on protein interaction networks and the phenotypes they regulate. We describe an analytical framework based on multiscale statistical mechanics that integrates genomic and biophysical data to model the human SH2-phosphoprotein network in normal and cancer cells. We apply our approach to data in The Cancer Genome Atlas (TCGA) and test model predictions experimentally. We find that mutations in phosphoproteins often create new interactions but that mutations in SH2 domains result almost exclusively in loss of interactions. Some of these mutations eliminate all interactions but many cause more selective loss, thereby rewiring specific edges in highly connected subnetworks. Moreover, idiosyncratic mutations appear to be as functionally consequential as recurrent mutations. By synthesizing genomic, structural, and biochemical data our framework represents a new approach to the interpretation of genetic variation.
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    Biophysical Prediction of Protein-Peptide Interactions and Signaling Networks Using Machine Learning
    (Springer Science and Business Media LLC, 2020-01-06) Cunningham, Joseph; Koytiger, Grigoriy; Sorger, Peter; AlQuraishi, Mohammed
    In mammalian cells, much of signal transduction is mediated by weak protein-protein interactions between globular peptide-binding domains (PBDs) and unstructured peptidic motifs in partner proteins. The number and diversity of these PBDs (over 1,800 are known), low binding affinities, and sensitivity of binding properties to minor sequence variation represent a substantial challenge to experimental and computational analysis of PBD specificity and the networks PBDs create. Here we introduce a bespoke machine learning approach, hierarchical statistical mechanical modelling (HSM), capable of accurately predicting the affinities of PBD-peptide interactions across multiple protein families. By synthesizing biophysical priors within a modern machine learning framework, HSM outperforms existing computational methods and high-throughput experimental assays. HSM models are interpretable in familiar biophysical terms at three spatial scales: the energetics of protein-peptide binding, the multi-dentate organization of protein-protein interactions, and the global architecture of signaling networks.