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KOÇ UNIVERSITY

GRADUATE SCHOOL OF SCIENCES & ENGINEERING

MOLECULAR BIOLOGY AND GENETICS

MS THESIS DEFENSE BY AYŞE SEDA YAZGILI

 

Title: Molecular Dynamics Simulations and Computational Analysis of K-Ras4B and c-Raf Interaction

 

Speaker: Ayşe Seda Yazgılı

 

Time: October 15th, 2018, 10:00 AM

 

Place: MF-Z72

Koç University

Rumeli Feneri Yolu

Sariyer, Istanbul

Thesis Committee Members:

Prof. Özlem Keskin (Advisor, Koc University)

Prof. Attila Gürsoy (co-advisor, Koç University)

Prof. Halil Kavaklı (Koç University)

Assist. Prof. Elif Nur Fırat Karalar (Koc University)

Assist. Prof. Sefer Baday (Istanbul Technical University)

 

Abstract:

 

Ras proteins are activated through their upstream effectors. Upon activation Ras proteins recruit to the plasma membrane and activate downstream effectors. Activated downstream effectors, then induces other proteins and this signaling cascades lead several responses within the cell. Although Ras proteins are activated through guanine exchange factor protein, specific mutations on Ras results with constitutively activated Ras. Those mutations found in many cancer types and several developmental diseases. Therefore, targeting the mutations on Ras has been the main focus in the treatment of Ras-related diseases. However, Ras proteins are still classified as “undruggable protein”. Effects of the mutations on Ras proteins and the interaction dynamics between their effectors are unclear. In this thesis, K-Ras4B and c-Raf interaction studied within two systems through molecular dynamics simulations. Computationally, I predicted K-Ras4B and c-Raf interaction by using PRISM (PRotein Interactions by Structural Matching). Residues on Ras and Raf identified using HotRegion. The results gave an idea about the specific amino acids involved in K-Ras4B and c-Raf interaction. To confirm the predictions, R41E/K42D double charge reversal mutations, called B3 mutation, were introduced to the control (G12D). I performed MD simulations on control and B3 mutated subsystems. In the first system, which contains K-Ras4B1-166, the mutation has not affected the energy levels significantly. Thus, I added hyper variable region to the system. The second system showed an unexpected result. Binding free energy of control and B3 mutant calculated as 1.1 ± 7.3 and -16.3 ± 7.5 kcal/mol, respectively. The results indicate that the B3 mutation is energetically more favorable. The unexpected energy levels can be studied further by introducing a membrane and a cysteine rich domain (CRD) to the system. Interaction dynamics of Ras with its other effectors, such as PI3K, can also be studied in the future to compare whether the B3 mutation prefer one Ras signaling pathway over another.

 

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