How Anionic Lipids Affect Spatiotemporal Properties of KRAS4B on Model Membranes

Area of Science:

• Cellular Biology
• Biophysics
• Molecular Dynamics

Background:

• RAS proteins are GTPases regulating cellular signaling.
• Anionic lipids impact RAS spatiotemporal properties, affecting dimerization and signaling fidelity.
• Understanding lipid-RAS interactions is crucial for deciphering signaling pathway regulation.

Purpose of the Study:

• To investigate the effects of anionic lipids (POPS and PIP2) on KRAS4B spatiotemporal properties.
• To analyze KRAS4B orientation, kinetics, and RAF kinase binding on different lipid membranes.
• To quantify the influence of PIP2 and POPS on KRAS4B dimerization rates.

Main Methods:

• All-atom molecular dynamics simulations of KRAS4B on POPC membranes with POPS and PIP2.
• Analysis of KRAS4B orientation space and kinetic states.
• Green's function reaction dynamics simulations to calculate dimerization rates.

Main Results:

• KRAS4B exhibited slower and more distinct kinetics on PIP2-rich membranes compared to POPS-rich membranes.
• PIP2 membranes induced a third kinetic orientation state for KRAS4B.
• RAF kinase binding probability remained unchanged, but orientation states influenced binding modes.
• KRAS4B dimerization rate was 12.5% slower on PIP2-mixed membranes.

Conclusions:

• Anionic lipid composition significantly modulates KRAS4B spatiotemporal dynamics and orientation.
• PIP2, in particular, alters KRAS4B kinetics and its interaction potential with RAF kinase.
• These findings provide insights into how membrane environment influences RAS signaling pathway activation.