Ras proteins are membrane-bound signal transducers that regulate cell growth, survival, and differentiation. Ras' normal function requires it to cycle between active, guanosine triphosphate (GTP)-bound and inactive, guanosine diphosphate (GDP)-bound states, and mutations that lock Ras into active conformations are implicated in cancer progression. We use massively repeated atomic-scale molecular dynamics simulations to define the behavior of K-Ras4B at the cell membrane. These simulations reveal that Ras' spatial arrangement can be understood in terms of distinct states, which are influenced more heavily by lipid composition than by the bound nucleotide. Because each state has a unique pattern of binding competence for various upstream regulators and downstream effectors, the resulting map of Ras' disposition at the cell membrane is a useful tool for future drug discovery efforts. It also provides a theoretical framework to predict relationships between lipid composition and the likelihood of Ras dimerization.<br/>

Conformational dynamics of full length Ras on the millisecond timescale

2019 Spring National Meeting

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