Researcher: Weako, Jackson
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Weako, Jackson
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Publication Metadata only Mutational effects on protein-protein interactions(World Scientific Publishing Co., 2020) Department of Computer Engineering; Department of Chemical and Biological Engineering; N/A; Gürsoy, Attila; Keskin, Özlem; Weako, Jackson; Faculty Member; Faculty Member; Master Student; Department of Computer Engineering; Department of Chemical and Biological Engineering; College of Engineering; College of Engineering; Graduate School of Sciences and Engineering; 8745; 26605; N/AInteratomically, protein’s ability to enact careful and tight interactions with its biomolecular partners is pivotal necessitating proper biological function. Protein-protein interactions (PPIs) are paramount in biological processes as manifested by their tenaciouscellular duties. Protein interfaces are the contact regions between proteins. The interface residues are under constant evolutionary restriction than surface residues. Variations in interface residues which alter binding affinity of proteins may lead to pronounce perturbation or absolute annulment of their functions, potentially resulting in diseases. Hence, wealth of investigations on mutational consequences of PPIs has evolved. The availability of both experimental and computational techniques to assess the effects of mutations on protein-protein binding affinities is essential for varieties of biomedical applications, spurring establishment of various mutational databases. Here, handy experimental and computational methods for detecting/predicting consequences of mutations on PPIs have been explored. Also, protocols and features of proteins utilized by these techniques have been elaborated and updates on mutational databases have been provided. Finally, case studies on mutations emerging at PPI interfaces and their involvements in human-related diseases such as cancer have been provided.Publication Metadata only Examining the stability of binding modes of the co-crystallized inhibitors of human HDAC8 by molecular dynamics simulation(Taylor & Francis Inc, 2020) Uba, Abdullahi İbrahim; Yelekçi, Kemal; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Weako, Jackson; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745Histone deacetylase (HDAC) 8 has been implicated as a potential therapeutic target in a variety of cancers, neurodegenerative disorders, metabolic dysregulation and autoimmune and inflammatory diseases. Several nonselective HDAC inhibitors have been co-crystallized with HDAC8. Molecular dynamics (MD) studies may yield valuable information on the structural stabilities of the complexes over time as determined by various pharmacophore features of the co-crystallized inhibitors. Here, using 11 unmodified X-ray crystal structures of human HDAC8 (complexes) structure-based pharmacophore models were built and clustered based on distance - a function of the number of common pharmacophore features and the root-mean-squared displacement between the matching features. Based on this information, a total of seven complexes (1T64, 1W22, 3RQD, 3SFF, 3F0R, 5VI6 and 5FCW) were submitted to unrestrained 50 ns-MD simulations using nanoscale MD (NAMD) software. 1T64 (HDAC8 in complex with TSA) was found to show the highest stability over time, presumably because of the TSA's ability to span HDAC8 catalytic channel and form a strong ionic interaction with zinc metal ion. Other stable complexes were 1W22, 3SFF, 3F0R and 5FCW. However, 3RQD and 5VI6 showed relative instability over 50 ns time period. This may be attributed to bulkiness of the capping groups of both largazole thiol and trapoxin A, making them unable to fit well into the active site of HDAC8. They rather formed steric clashes with residues on loop regions near the entrance to the channel. Thus, 1T64 and similar crystal structures may be good candidates for HDAC8 structural dynamics studies and inhibitor design.Publication Open Access The structural basis of Akt PH domain interaction with calmodulin(Elsevier, 2021) Jang, Hyunbum; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Weako, Jackson; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 26605; 8745Akt plays a key role in the Ras/PI3K/Akt/mTOR signaling pathway. In breast cancer, Akt translocation to the plasma membrane is enabled by the interaction of its pleckstrin homology domain (PHD) with calmodulin (CaM). At the membrane, the conformational change promoted by PIP3 releases CaM and facilitates Thr308 and Ser473 phosphorylation and activation. Here, using modeling and molecular dynamics simulations, we aim to figure out how CaM interacts with Akt's PHD at the atomic level. Our simulations show that CaM-PHD interaction is thermodynamically stable and involves a beta-strand rather than an alpha-helix, in agreement with NMR data, and that electrostatic and hydrophobic interactions are critical. The PHD interacts with CaM lobes; however, multiple modes are possible. IP4, the polar head of PIP3, weakens the CaM-PHD interaction, implicating the release mechanism at the plasma membrane. Recently, we unraveled the mechanism of PI3K alpha activation at the atomistic level and the structural basis for Ras role in the activation. Here, our atomistic structural data clarify the mechanism of how CaM interacts, delivers, and releases Akt-the next node in the Ras/PI3K pathway-at the plasma membrane.