Identification of functional substates of KRas during GTP hydrolysis with enhanced sampling simulations

Zeng, Juan; Chen, Jian; Xia, Fei; Cui, Qiang; Deng, Xianming; Xu, Xin

doi:10.1039/d2cp00274d

Cited by 12 publications

(26 citation statements)

References 87 publications

(148 reference statements)

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“…Ras oncoproteins can exist in different nucleotide-bound and mutant forms in cells, all of which are inherently flexible 7,[29][30][31][32][33]54,55 populating a diverse set of conformations including many that possess druggable pockets unobserved in the ground structures. To date, studies that took advantage of the cryptic pockets 10,[13][14][15]38,56 for targeting have significantly advanced the therapeutics development against Ras and proved covalent modification a feasible strategy for direct inhibition of Ras(G12C)ÁGDP.…”

Section: Discussionmentioning

confidence: 99%

“…26,27 Conformational exchange was also captured by relaxation-based NMR in the inactive GDP-bound state, which however occurs on a much faster timescale. 28 Previous molecular dynamics and enhanced sampling simulations 7,11,[29][30][31][32][33] suggest that the cryptic pockets can commonly pre-exist in different nucleotide-bound and mutant forms. However, it remains unclear how the mutations and activation states alter the ''invisible'' vulnerable conformers of Ras leading to the differential druggabilities noted in recent drug development efforts.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective druggabilities

Wang

Liu

et al. 2023

Phys. Chem. Chem. Phys.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective druggabilities

Wang

Liu

et al. 2023

Phys. Chem. Chem. Phys.

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“…The experimental structures and computational studies stemming from multiple work teams suggested that G13D mutants in the three isoforms (HRAS, KRAS and NRAS) had an altered active site and conformational changes of the switch domains that affect the stability of the nucleotide-binding pocket [ 8 , 32 , 33 , 34 ]. More previous studies revealed that mutations different from codons 12, 13, and 61 also exerted significant effect on the conformation states of the switch domains and the nucleotide binding [ 12 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Despite these successes, molecular mechanism of mutation-induced conformational state changes of the switch domains from KRAS are still insufficient currently.…”

Section: Introductionmentioning

confidence: 99%

Impacts of Mutations in the P-Loop on Conformational Alterations of KRAS Investigated with Gaussian Accelerated Molecular Dynamics Simulations

et al. 2023

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G12 mutations heavily affect conformational transformation and activity of KRAS. In this study, Gaussian accelerated molecular dynamics (GaMD) simulations were performed on the GDP-bound wild-type (WT), G12A, G12D, and G12R KRAS to probe mutation-mediated impacts on conformational alterations of KRAS. The results indicate that three G12 mutations obviously affect the structural flexibility and internal dynamics of the switch domains. The analyses of the free energy landscapes (FELs) suggest that three G12 mutations induce more conformational states of KRAS and lead to more disordered switch domains. The principal component analysis shows that three G12 mutations change concerted motions and dynamics behavior of the switch domains. The switch domains mostly overlap with the binding region of KRAS to its effectors. Thus, the high disorder states and concerted motion changes of the switch domains induced by G12 mutations affect the activity of KRAS. The analysis of interaction network of GDP with KRAS signifies that the instability in the interactions of GDP and magnesium ion with the switch domain SW1 drives the high disordered state of the switch domains. This work is expected to provide theoretical aids for understanding the function of KRAS.

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“…59 Markov State Model (MSM) analysis, Replica Exchange MD, and Principal Component Analysis (PCA) have also been applied specifically to K- Ras4B. 47,48,50,53…”

Section: Introductionmentioning

confidence: 99%

Decrypting the languages of allostery in membrane-bound K-Ras4B using four complementaryin silicoapproaches

Castelli

Marchetti²,

Serapian

et al. 2023

Preprint

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Proteins are evolved molecular machines whose diverse biochemical functions are (also) dynamically regulated by allostery, through which even faraway protein residues can conformationally communicate. Allostery can express itself in different ways, akin to different "languages": allosteric control pathways predominating in an unperturbed protein are superseded by others as soon as a perturbation arises—e.g, mutation—that alters its function (pathologically or not). Accurately modeling these often-unintuitive phenomena could therefore help explain functional changes in a specific protein whenever they are unclear. Unbiased molecular dynamics (MD) simulations are a possibility; however, since allostery can operate at longer timescales than those accessible by MD, simulations require integration with a reliable method able to, e.g., detect regions of incipient allosteric change, or likely perturbation pathways. Several such (valid) methods exist, but are typically applied singularly, only yielding a partial ("monolinguistic") picture of allostery: we argue their joint application could significantly enrich this picture. To prove this, we perform unbiased MD simulations (~100 μs) of the widely studied, allosterically active oncotarget K-Ras4B, solvated and embedded in a phospholipid membrane, proceeding to decrypt its allostery using four showcase "languages": Distance Fluctuation analysis and the Shortest Path Map capture allosteric communication hotspots at equilibrium; Anisotropic Thermal Diffusion and Dynamic Non-Equilibrium MD assess them once the GTP that oncogenically activates K-Ras4B is, respectively, either superheated or hydrolyzed. "Languages" provide a uniquely articulate, mutually coherent, experimentally consistent picture of allostery in K-Ras4B. At equilibrium, pathways stretch from the membrane-embedded hypervariable region all the way to the active site, touching known flexible allosteric "switches" and proposed pockets. Upon GTP cleavage/perturbation, known to inactivate K-Ras4B, allosteric signals most reverberate on switches and interfaces that recruit effector proteins. Our work highlights the benefits of integrating different allostery detection methods, even in conjunction with unbiased MD.

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Identification of functional substates of KRas during GTP hydrolysis with enhanced sampling simulations

Abstract: As the hub of major signaling pathways, Ras proteins are implicated in 19% of tumor-caused cancers due to perturbations in their conformational and/or catalytic properties. Despite numerous studies, the functions...

Cited by 12 publications

References 87 publications

Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective druggabilities

Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective druggabilities

Impacts of Mutations in the P-Loop on Conformational Alterations of KRAS Investigated with Gaussian Accelerated Molecular Dynamics Simulations

Decrypting the languages of allostery in membrane-bound K-Ras4B using four complementaryin silicoapproaches

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