Millisecond molecular dynamics simulations of KRas-dimer formation and interfaces
Abstract
Ras dimers have been proposed as building blocks for initiating the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cellular signaling pathway. To better examine the structure of possible dimer interfaces, the dynamics of Ras dimerization, and its potential signaling consequences, we performed molecular dynamics simulations totaling 1 ms of sampling, using an all-atom model of two full-length, farnesylated, guanosine triphosphate (GTP)-bound, wild-type KRas4b proteins diffusing on 29%POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine)-mixed POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) membranes. Furthermore, our simulations unveil an ensemble of thermodynamically weak KRas dimers spanning multiple conformations. The most stable conformations, having the largest interface areas, involve helix α2 and a hypervariable region (HVR). Among the dimer conformations, we found that the HVR of each KRas has frequent interactions with various parts of the dimer, thus potentially mediating the dimerization. Some dimer configurations have one KRas G-domain elevated above the lipid bilayer surface by residing on top of the other G-domain, thus likely contributing to the recruitment of cytosolic Raf kinases in the context of a stably formed multi-protein complex. We identified a variant of the α4-α5 KRas-dimer interface that is similar to the interfaces obtained with fluorescence resonance energy transfer (FRET) data of HRas on lipid bilayers. Interestingly, we found twomore »
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA)
- OSTI Identifier:
- 2008007
- Alternate Identifier(s):
- OSTI ID: 1883784; OSTI ID: 1961917
- Grant/Contract Number:
- AC05-00OR22725; AC52-06NA25396
- Resource Type:
- Published Article
- Journal Name:
- Biophysical Journal
- Additional Journal Information:
- Journal Name: Biophysical Journal Journal Volume: 121 Journal Issue: 19; Journal ID: ISSN 0006-3495
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Ngo, Van A., and Garcia, Angel E. Millisecond molecular dynamics simulations of KRas-dimer formation and interfaces. United States: N. p., 2022.
Web. doi:10.1016/j.bpj.2022.04.026.
Ngo, Van A., & Garcia, Angel E. Millisecond molecular dynamics simulations of KRas-dimer formation and interfaces. United States. https://doi.org/10.1016/j.bpj.2022.04.026
Ngo, Van A., and Garcia, Angel E. Sat .
"Millisecond molecular dynamics simulations of KRas-dimer formation and interfaces". United States. https://doi.org/10.1016/j.bpj.2022.04.026.
@article{osti_2008007,
title = {Millisecond molecular dynamics simulations of KRas-dimer formation and interfaces},
author = {Ngo, Van A. and Garcia, Angel E.},
abstractNote = {Ras dimers have been proposed as building blocks for initiating the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cellular signaling pathway. To better examine the structure of possible dimer interfaces, the dynamics of Ras dimerization, and its potential signaling consequences, we performed molecular dynamics simulations totaling 1 ms of sampling, using an all-atom model of two full-length, farnesylated, guanosine triphosphate (GTP)-bound, wild-type KRas4b proteins diffusing on 29%POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine)-mixed POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) membranes. Furthermore, our simulations unveil an ensemble of thermodynamically weak KRas dimers spanning multiple conformations. The most stable conformations, having the largest interface areas, involve helix α2 and a hypervariable region (HVR). Among the dimer conformations, we found that the HVR of each KRas has frequent interactions with various parts of the dimer, thus potentially mediating the dimerization. Some dimer configurations have one KRas G-domain elevated above the lipid bilayer surface by residing on top of the other G-domain, thus likely contributing to the recruitment of cytosolic Raf kinases in the context of a stably formed multi-protein complex. We identified a variant of the α4-α5 KRas-dimer interface that is similar to the interfaces obtained with fluorescence resonance energy transfer (FRET) data of HRas on lipid bilayers. Interestingly, we found two arginine fingers, R68 and R149, that directly interact with the beta-phosphate of the GTP bound in KRas, in a manner similar to what is observed in a crystal structure of GAP-HRas complex, which can facilitate the GTP hydrolysis via the arginine finger of GTPase-activating protein (GAP).},
doi = {10.1016/j.bpj.2022.04.026},
journal = {Biophysical Journal},
number = 19,
volume = 121,
place = {United States},
year = {Sat Oct 01 00:00:00 EDT 2022},
month = {Sat Oct 01 00:00:00 EDT 2022}
}
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