| Autor: |
Zhiping Yu, Zhen Wang, Xiuzhen Cui, Zanxia Cao, Wanyunfei Zhang, Kunxiao Sun, Guodong Hu |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Molecules, Vol 29, Iss 3, p 645 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
1420-3049 |
| DOI: |
10.3390/molecules29030645 |
| Popis: |
The HRAS protein is considered a critical target for drug development in cancers. It is vital for effective drug development to understand the effects of mutations on the binding of GTP and GDP to HRAS. We conducted Gaussian accelerated molecular dynamics (GaMD) simulations and free energy landscape (FEL) calculations to investigate the impacts of two mutations (A59E and K117R) on GTP and GDP binding and the conformational states of the switch domain. Our findings demonstrate that these mutations not only modify the flexibility of the switch domains, but also affect the correlated motions of these domains. Furthermore, the mutations significantly disrupt the dynamic behavior of the switch domains, leading to a conformational change in HRAS. Additionally, these mutations significantly impact the switch domain’s interactions, including their hydrogen bonding with ligands and electrostatic interactions with magnesium ions. Since the switch domains are crucial for the binding of HRAS to effectors, any alterations in their interactions or conformational states will undoubtedly disrupt the activity of HRAS. This research provides valuable information for the design of drugs targeting HRAS. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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