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Comparative MD simulations and advanced analytics based studies on wild-type and hot-spot mutant A59G HRas
- Source :
- PLoS ONE, PLoS ONE, Vol 15, Iss 10, p e0234836 (2020)
- Publication Year :
- 2020
- Publisher :
- Public Library of Science (PLoS), 2020.
-
Abstract
- The Ras family of proteins is known to play an important role in cellular signal transduction. The oncoprotein Ras is also found to be mutated in ∼90% of the pancreatic cancers, of which G12V, G13V, A59G and Q61L are the known hot-spot mutants. These ubiquitous proteins fall in the family of G-proteins, and hence switches between active GTP bound and inactive GDP bound states, which is hindered in most of its oncogenic mutant counterparts. Moreover, Ras being a GTPase has an intrinsic property to hydrolyze GTP to GDP, which is obstructed due to mutations and lends the mutants stuck in constitutively active state leading to oncogenic behavior. In this regard, the present study aims to understand the dynamics involved in the hot-spot mutant A59G-Ras using long classical MD simulations (∼10µs) and comparing the same with its wild-type counterpart. Advanced analytics using Markov State Model (MSM) based approach has been deployed to comparatively understand the transition path for the wild-type and mutant systems. Roles of crucial residues like Tyr32, Gln61 and Tyr64 have also been established using multivariate PCA analyses. Furthermore, this multivariate PCA analysis also provides crucial features which may be used as reaction coordinates for biased simulations for further studies. The absence of formation of pre-hydrolysis network is also reported for the mutant conformation, using the distance-based analyses (between crucial residues) of the conserved regions. The implications of this study strengthen the hypothesis that the disruption of the pre-hydrolysis network in the mutant A59G ensemble might lead to permanently active oncogenic conformation in the mutant conformers.
- Subjects :
- 0301 basic medicine
GTP'
Mutant
Constitutively active
GTPase
Molecular Dynamics
Biochemistry
Metastasis
Mathematical and Statistical Techniques
Computational Chemistry
Chemical reactions
Basic Cancer Research
Biochemical Simulations
Medicine and Health Sciences
Principal Component Analysis
Crystallography
Multidisciplinary
Chemistry
Hydrolysis
Physics
Simulation and Modeling
Statistics
Condensed Matter Physics
Cellular signal transduction
Cell biology
Oncology
Physical Sciences
Crystal Structure
Medicine
Guanosine Triphosphate
Research Article
Science
Hot spot (veterinary medicine)
Molecular Dynamics Simulation
Research and Analysis Methods
Guanosine Diphosphate
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Solid State Physics
Humans
HRAS
Statistical Methods
State model
030102 biochemistry & molecular biology
Wild type
Biology and Life Sciences
Computational Biology
GTP hydrolysis
030104 developmental biology
Multivariate Analysis
Mutation
Mathematics
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- PLOS ONE
- Accession number :
- edsair.doi.dedup.....129b838f608a1e75797b36ec82276206