Biomedical Sciences and Engineering PhD Thesis Defense by Sezen Vatansever

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KOÇ UNIVERSITY

GRADUATE SCHOOL OF SCIENCES & ENGINEERING

BIOMEDICAL SCIENCES AND ENGINEERING

PhD THESIS DEFENSE BY SEZEN VATANSEVER

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Title: A Comprehensive Study of K-Ras Protein and Its Oncogenic Mutations: A Dynamic Point of View

Speaker: Sezen Vatansever

Time: 21 August 2017 9:30

Place: ENG 208

Koç University

Rumeli Feneri Yolu

Sariyer, Istanbul

Thesis Committee Members:

Prof. Dr. Burak ERMAN (Advisor, Koc University)

Prof. Dr. Füsun CAN (Koc University)

Asst. Prof. Alper UZUN (Koc University)

Prof. Dr. Kemal YELEKÇİ (Kadir Has University)

Assoc. Prof. Ebru Demet Akten (Kadir Has University)

Abstract:

K-Ras is the most frequently mutated protein in human cancers driving cancer initiation, progression and drug resistance, directly leading to nearly a million deaths per year. Sadly, there are still no drugs in that directly target mutant K-Ras in the clinic. Recent studies utilizing dynamics information show promising results for selectively targeting it. However, despite extensive characterization, the regulatory mechanisms of K-Ras dynamics remain elusive. Since protein function is related to its dynamics, understanding these mechanisms can present novel opportunities for identifying target sites on mutant K-Ras surface. In this work, we investigate the regulation mechanisms of K-Ras dynamics and the effects of nucleotide binding and mutations on these mechanisms using extensive molecular dynamics (MD) simulations. We applied different MD simulation data analysis techniques to compare the dynamic characteristics of both active and inactive forms of wild-type K-RasWT and mutant K-RasG12D, the most recurrent mutant in cancer patients. Our results on K-RasWT showed excellent agreement with experimental data and served as a reference point for K-RasG12D analysis. Then, we demonstrated how G12D mutation induces structural and conformational changes that result in characteristic correlated motions in active K-RasG12D. Moreover, we developed a novel conditional time-delayed correlations (CTC) based approach to predict causal relationships in regulation of K-Ras dynamics. CTC analysis identified the regulatory sites that control K-Ras dynamics. Finally, we identified a novel drug target pocket in active K-RasG12D and screened a small molecule library against it using docking techniques. Our study draws a complete picture of the regulation of K-Ras dynamics. We anticipate that the identified regulatory sites on active K-RasG12D can present novel opportunities for direct targeting of K-RasG12D in future drug discovery efforts.