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Sökning: WFRF:(Gapsys Vytautas)

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1.
  • Chakrabarti, Kalyan S., et al. (författare)
  • A litmus test for classifying recognition mechanisms of transiently binding proteins
  • 2022
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Partner recognition in protein binding is critical for all biological functions, and yet, delineating its mechanism is challenging, especially when recognition happens within microseconds. We present a theoretical and experimental framework based on straight-forward nuclear magnetic resonance relaxation dispersion measurements to investigate protein binding mechanisms on sub-millisecond timescales, which are beyond the reach of standard rapid-mixing experiments. This framework predicts that conformational selection prevails on ubiquitin’s paradigmatic interaction with an SH3 (Src-homology 3) domain. By contrast, the SH3 domain recognizes ubiquitin in a two-state binding process. Subsequent molecular dynamics simulations and Markov state modeling reveal that the ubiquitin conformation selected for binding exhibits a characteristically extended C-terminus. Our framework is robust and expandable for implementation in other binding scenarios with the potential to show that conformational selection might be the design principle of the hubs in protein interaction networks.
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2.
  • Gapsys, Vytautas, et al. (författare)
  • Accurate absolute free energies for ligand-protein binding based on non-equilibrium approaches
  • 2021
  • Ingår i: Communications Chemistry. - : Springer Nature. - 2399-3669. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • Molecular dynamics-based approaches to calculate absolute protein-ligand binding free energy often rely on equilibrium free energy perturbation (FEP) protocols. Here, the authors study ligands binding to bromodomains and T4 lysozyme and find that both equilibrium and non-equilibrium approaches converge to the same results with the non-equilibrium method converging faster than FEP. The accurate calculation of the binding free energy for arbitrary ligand-protein pairs is a considerable challenge in computer-aided drug discovery. Recently, it has been demonstrated that current state-of-the-art molecular dynamics (MD) based methods are capable of making highly accurate predictions. Conventional MD-based approaches rely on the first principles of statistical mechanics and assume equilibrium sampling of the phase space. In the current work we demonstrate that accurate absolute binding free energies (ABFE) can also be obtained via theoretically rigorous non-equilibrium approaches. Our investigation of ligands binding to bromodomains and T4 lysozyme reveals that both equilibrium and non-equilibrium approaches converge to the same results. The non-equilibrium approach achieves the same level of accuracy and convergence as an equilibrium free energy perturbation (FEP) method enhanced by Hamiltonian replica exchange. We also compare uni- and bi-directional non-equilibrium approaches and demonstrate that considering the work distributions from both forward and reverse directions provides substantial accuracy gains. In summary, non-equilibrium ABFE calculations are shown to yield reliable and well-converged estimates of protein-ligand binding affinity.
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  • Resultat 1-2 av 2

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