Free energy evaluation of the p53-Mdm2 complex from unbinding work measured by dynamic force spectroscopy

Literature Information

Publication Date 2010-12-10
DOI 10.1039/C0CP01474E
Impact Factor 3.676
Authors

Anna Rita Bizzarri, Salvatore Cannistraro


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Abstract

The complex between the tumor suppressor p53 and its down-regulator Mdm2 has been studied by dynamic force spectroscopy and the unbinding data have been analyzed in the framework of the Jarzynski theoretical approach. Accordingly, the unbinding equilibrium free energy has been determined from the work done along several non-equilibrium paths from the bound to the unbound state in the single molecule regime. An unbinding free energy of −8.4 kcal mol−1 has been found for the complex; such a value is in a good agreement with that measured both in the bulk by isothermal titration calorimetry and that obtained from theoretical computing at the single molecule level. The determination of the unbinding free energy, together with the knowledge of the dissociation rate constant and energy barrier width, as previously obtained by dynamic force spectroscopy, adds rewarding insights on the energy landscape for this complex which is currently at the focus of anticancer drug design.

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Physical Chemistry Chemical Physics

Physical Chemistry Chemical Physics
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Physical Chemistry Chemical Physics (PCCP) is an international journal co-owned by 19 physical chemistry and physics societies from around the world. This journal publishes original, cutting-edge research in physical chemistry, chemical physics and biophysical chemistry. To be suitable for publication in PCCP, articles must include significant innovation and/or insight into physical chemistry; this is the most important criterion that reviewers and Editors will judge against when evaluating submissions. The journal has a broad scope and welcomes contributions spanning experiment, theory, computation and data science. Topical coverage includes spectroscopy, dynamics, kinetics, statistical mechanics, thermodynamics, electrochemistry, catalysis, surface science, quantum mechanics, quantum computing and machine learning. Interdisciplinary research areas such as polymers and soft matter, materials, nanoscience, energy, surfaces/interfaces, and biophysical chemistry are welcomed if they demonstrate significant innovation and/or insight into physical chemistry. Joined experimental/theoretical studies are particularly appreciated when complementary and based on up-to-date approaches.

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