Enhanced Exploration of Protein Conformational Space through Integration of Ultra-Coarse-Grained Models to Multiscale Workflows
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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Engineering topics
Oppelstrup, Tomas
Publications and source records attributed to Oppelstrup, Tomas.
Breaking the Molecular Dynamics Timescale Barrier Using a Wafer-Scale System
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Santos, Kylee↗
Cerebras TriLabs SC'24 paper Artifact Description
Artifact Description of the Cerebras TriLabs SC'24 conference paper. Include details and procedures for how to reproduce timing computations.
Oppelstrup, Tomas↗
Membrane lipids drive formation of KRAS4b-RAF1 RBDCRD nanoclusters on the membrane
The oncogene RAS, extensively studied for decades, presents persistent gaps in understanding, hindering the development of effective therapeutic strategies due to a lack of precise details on how RAS initiates MAPK signaling with RAF effector proteins at the plasma membrane. Recent advances in X-ray crystallography, cryo-EM, and super-resolution fluorescence microscopy offer structural and spatial insights, yet the molecular mechanisms involving protein-protein and protein-lipid interactions in RAS-mediated signaling require further characterization. This study utilizes single-molecule experimental techniques, nuclear magnetic resonance spectroscopy, and the computational Machine-Learned Modeling Infrastructure (MuMMI) to examine KRAS4b and RAF1 on a biologically relevant lipid bilayer. MuMMI captures long-timescale events while preserving detailed atomic descriptions, providing testable models for experimental validation. Both in vitro and computational studies reveal that RBDCRD binding alters KRAS lateral diffusion on the lipid bilayer, increasing cluster size and decreasing diffusion. RAS and membrane binding cause hydrophobic residues in the CRD region to penetrate the bilayer, stabilizing complexes through β-strand elongation. These cooperative interactions among lipids, KRAS4b, and RAF1 are proposed as essential for forming nanoclusters, potentially a critical step in MAP kinase signal activation.
59 BASIC BIOLOGICAL SCIENCES↗