ArticlePLoS computational biology2012
The role of conserved waters in conformational transitions of Q61H K-ras.
Article in PLoS computational biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 52 citations in OpenAlex.
- Insight into structural dynamics involved in activation mechanism of full length KRAS wild type and P-loop mutants.Heliyon · 2024Article
- Identification of New KRAS G12D Inhibitors through Computer-Aided Drug Discovery Methods.International journal of molecular sciences · 2022Article
- Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes.RSC advances · 2022Article
- Comparative MD simulations and advanced analytics based studies on wild-type and hot-spot mutant A59G HRas.PloS one · 2020Article
- Oncogenic G12D mutation alters local conformations and dynamics of K-Ras.Scientific reports · 2019Article
- Spatiotemporal Analysis of K-Ras Plasma Membrane Interactions Reveals Multiple High Order Homo-oligomeric Complexes.Journal of the American Chemical Society · 2017Article
- Article
- Hidden electrostatic basis of dynamic allostery in a PDZ domain.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Activation mechanisms of the first sphingosine-1-phosphate receptor.Protein science : a publication of the Protein Society · 2017Article
- Mixed-Probe Simulation and Probe-Derived Surface Topography Map Analysis for Ligand Binding Site Identification.Journal of chemical theory and computation · 2017Article
- Analysis of correlated mutations in Ras G-domain.Bioinformation · 2017Article
- Article
- Intrinsic K-Ras dynamics: A novel molecular dynamics data analysis method shows causality between residue pair motions.Scientific reports · 2016Article
- Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view.Chemical Society reviews · 2016Review
- Computational Equilibrium Thermodynamic and Kinetic Analysis of K-Ras Dimerization through an Effector Binding Surface Suggests Limited Functional Role.The journal of physical chemistry. B · 2016Article
- Comparison of the Conformations of KRAS Isoforms, K-Ras4A and K-Ras4B, Points to Similarities and Significant Differences.The journal of physical chemistry. B · 2016Article
- Stay Wet, Stay Stable? How Internal Water Helps the Stability of Thermophilic Proteins.The journal of physical chemistry. B · 2015Article
- pMD-Membrane: A Method for Ligand Binding Site Identification in Membrane-Bound Proteins.PLoS computational biology · 2015Article
- Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains.The journal of physical chemistry. B · 2015Article
- Binding hotspots on K-ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis.Proteins · 2015Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
To investigate the stability and functional role of long-residence water molecules in the Q61H variant of the signaling protein K-ras, we analyzed all available Ras crystal structures and conformers derived from a series of independent explicit solvent molecular dynamics (MD) simulations totaling 1.76 µs. We show that the protein samples a different region of phase space in the presence and absence of several crystallographically conserved and buried water molecules. The dynamics of these waters is coupled with the local as well as the global motions of the protein, in contrast to less buried waters whose exchange with bulk is only loosely coupled with the motion of loops in their vicinity. Aided by two novel reaction coordinates involving the distance (d) between the C(α) atoms of G60 at switch 2 and G10 at the P-loop and the N-C(α)-C-O dihedral (ξ) of G60, we further show that three water molecules located in lobe1, at the interface between the lobes and at lobe2, are involved in the relative motion of residues at the two lobes of Q61H K-ras. Moreover, a d/ξ plot classifies the available Ras x-ray structures and MD-derived K-ras conformers into active GTP-, intermediate GTP-, inactive GDP-bound, and nucleotide-free conformational states. The population of these states and the transition between them is modulated by water-mediated correlated motions involving the functionally critical switch 2, P-loop and helix 3. These results suggest that water molecules act as allosteric ligands to induce a population shift among distinct switch 2 conformations that differ in effector recognition.
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