Revealing the favorable dissociation pathway of type II kinase inhibitors via enhanced sampling simulations and two-end-state calculations

Sun, Huiyong; Tian, Sheng; Zhou, Shunye; Li, Youyong; Li, Dan; Xu, Lei; Shen, Meifen; Pan, Peichen; Hou, Tingjun

doi:10.1038/srep08457

Cited by 75 publications

(63 citation statements)

References 57 publications

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“…4), as well as for other systems (27). In some applications, MDeNM was shown to perform better than other well-established enhanced sampling methods such as metadynamics or umbrella sampling (27,(41)(42)(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 97%

Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

Floquet

Costa

Batista

et al. 2015

Biophysical Journal

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Cyclin-dependent kinases (CDKs) and their associated regulatory cyclins are central for timely regulation of cell-cycle progression. They constitute attractive pharmacological targets for development of anticancer therapeutics, since they are frequently deregulated in human cancers and contribute to sustained, uncontrolled tumor proliferation. Characterization of their structural/dynamic features is essential to gain in-depth insight into structure-activity relationships. In addition, the identification of druggable pockets or key intermediate conformations yields potential targets for the development of novel classes of inhibitors. Structural studies of CDK2/cyclin A have provided a wealth of information concerning monomeric/heterodimeric forms of this kinase. There is, however, much less structural information for other CDK/cyclin complexes, including CDK4/cyclin D1, which displays an alternative (open) position of the cyclin partner relative to CDK, contrasting with the closed CDK2/cyclin A conformation. In this study, we carried out normal-mode analysis and enhanced sampling simulations with our recently developed method, molecular dynamics with excited normal modes, to understand the conformational equilibrium on these complexes. Interestingly, the lowest-frequency normal mode computed for each complex described the transition between the open and closed conformations. Exploration of these motions with an explicit-solvent representation using molecular dynamics with excited normal modes confirmed that the closed conformation is the most stable for the CDK2/cyclin A complex, in agreement with their experimentally available structures. On the other hand, we clearly show that an open↔closed equilibrium may exist in CDK4/cyclin D1, with closed conformations resembling that captured for CDK2/cyclin A. Such conformational preferences may result from the distinct distributions of frustrated contacts in each complex. Using the same approach, the putative roles of the Thr(160) phosphoryl group and the T-loop conformation were investigated. These results provide a dynamic view of CDKs revealing intermediate conformations not yet characterized for CDK members other than CDK2, which will be useful for the design of inhibitors targeting critical conformational transitions.

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Section: Discussionmentioning

confidence: 97%

Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

Floquet

Costa

Batista

et al. 2015

Biophysical Journal

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“…28–36 For example, a recent study with metadynamics and Markov state model cast light on the rate-limiting step of the inhibitor unbinding process from p38 α , 37 and research with umbrella sampling indicated the allosteric channel as the preferred dissociation pathway for type-II and -III inhibitors of p38 α . 38 Besides p38 α , different enhanced sampling simulations were used to sample dissociation of inhibitors from kinase family. 39–49 The adaptive biasing force (ABF) was used to investigate the unbinding process for inhibitors of ALK tyrosine kinase.…”

Section: Introductionmentioning

confidence: 99%

“…When a type-II or -III inhibitor binds to the allosteric pocket, existing studies suggested another possible dissociation pathway known as the allosteric-pocket channel. 38 This study aims to reveal key interactions and possible protein rearrangement that contribute significantly to dissociation energy barrier and rate determination. We applied two enhanced sampling methods, accelerated MD (AMD), and the newly developed pathway search guided by internal motions (PSIM) method to find pathways of ligands, type-I inhibitors SB2 and SK8, type-II inhibitor BIRB796, and type-III inhibitor LIG4, unbinding from p38 α .…”

Section: Introductionmentioning

confidence: 99%

Role of Molecular Interactions and Protein Rearrangement in the Dissociation Kinetics of p38α MAP Kinase Type-I/II/III Inhibitors

You

Chang

2018

J. Chem. Inf. Model.

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Understanding the governing factors of fast or slow inhibitor binding/unbinding assists in developing drugs with preferred kinetic properties. For inhibitors with the same binding affinity targeting different binding sites of the same protein, the kinetic behavior can profoundly differ. In this study, we investigated unbinding kinetics and mechanisms of fast (type-I) and slow (type-II/III) binders of p38α mitogen-activated protein kinase, where the crystal structures showed that type-I and type-II/III inhibitors bind to pockets with different conformations of the Asp-Phe-Gly (DFG) motif. The work used methods that combine conventional molecular dynamics (MD), accelerated molecular dynamics (AMD) simulations, and the newly developed pathway search guided by internal motions (PSIM) method to find dissociation pathways. The study focuses on revealing key interactions and molecular rearrangements that hinder ligand dissociation by using umbrella sampling and post-MD processing to examine changes in free energy during ligand unbinding. As anticipated, the initial dissociation steps all require breaking interactions that appeared in crystal structures of the bound complexes. Interestingly, for type-I inhibitors such as SB2, p38α keeps barrier-free conformational fluctuation in the ligand-bound complex and during ligand dissociation. In contrast, with a type-II/III inhibitor such as BIRB796, with the rearrangements of p38α in its bound state, ligand unbinding features energetically unfavorable protein–ligand concerted movement. Our results also show that the type-II/III inhibitors preferred dissociation pathways through the allosteric channel, which is consistent with an existing publication. The study suggests that the level of required protein rearrangement is one major determining factor of drug binding kinetics in p38α systems, providing useful information for development of inhibitors.

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“…Recent studies suggest that utilizing protein dynamics data is a successful approach for understanding the effects of mutations on the structure, dynamics and function of proteins [34][35][36] . Particularly in drug discovery, dynamics data from oncogenic proteins 22,[37][38][39][40] have helped identify cryptic or allosteric binding sites [41][42][43][44] . We hypothesized that dynamic regulatory mechanisms can best be explored by detailed analyses of their molecular dynamics (MD) simulation data, from which we can predict the regulatory relationships between residue pairs.…”

Section: Introductionmentioning

confidence: 99%

“…G12 is the most frequently mutated residue (89%), which most prevalently mutates to aspartate (G12D, 36%) followed by valine (G12V, 23%) and cysteine (G12C, 14%) 3,10 . This residue is located at the protein active site, which consists of a phosphate binding loop (P-loop, residues 10-17) and switch I (SI, residues [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] and II (SII, residues 60-74) regions. The active site residues are bound to the phosphate groups of GTP and are responsible for the GTPase function of K-Ras.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic G12D mutation alters local conformations and dynamics of K-Ras

Erman

Gümüş

2017

Preprint

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K-Ras is the most frequently mutated protein in human tumors. Activating K-Ras mutations drive cancer initiation, progression and drug resistance, directly leading to nearly a million deaths per year. To understand the mechanisms by which mutations alter K-Ras function, we need to understand their effects on protein dynamics. However, despite decades of research, how oncogenic mutations in K-Ras alter its conformation and dynamics remain to be understood. Here, we present how the most recurrent K-Ras oncogenic mutation, G12D, leads to structural, conformational and dynamical changes that lead to constitutively active KRas. We have developed a new integrated MD simulation data analysis approach to quantify such changes in a protein and applied it to K-Ras. Our results show that G12D mutation induces strong negative correlations between the fluctuations of SII and those of the P-loop, Switch I (SI) and α3 regions in K-Ras G12D . Furthermore, characteristic decay times of SII fluctuations significantly increase after G12D mutation. We have further identified causal relationships between correlated residue pairs in K-Ras G12D and show that the correlated motions in K-Ras dynamics are driven by SII fluctuations, which have the strongest negative correlations with other protein parts and the longest characteristic decay times in mutant KRas. Ours is arguably the first study that shows the causal relationships between residue pairs in K-Ras G12D , relates them to the decay times and correlates their fluctuations.

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Revealing the favorable dissociation pathway of type II kinase inhibitors via enhanced sampling simulations and two-end-state calculations

Cited by 75 publications

References 57 publications

Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

Conformational Equilibrium of CDK/Cyclin Complexes by Molecular Dynamics with Excited Normal Modes

Role of Molecular Interactions and Protein Rearrangement in the Dissociation Kinetics of p38α MAP Kinase Type-I/II/III Inhibitors

Oncogenic G12D mutation alters local conformations and dynamics of K-Ras

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