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De Vivo M.,Italian Institute of Technology | Bottegoni G.,Italian Institute of Technology | Berteotti A.,Italian Institute of Technology | Recanatini M.,University of Bologna | And 3 more authors.
Future Medicinal Chemistry | Year: 2011

Cyclin-dependent kinases (CDKs) are one of the most promising target families for drug discovery for several diseases, such as cancer and neurodegenerative disorders. Over the years, structural insights on CDKs have demonstrated high protein plasticity, with several cases where two or more structures of the same protein adopt different conformations. This has generated a great deal of interest in understanding the relationship between CDK structure and function. Here, we highlight how computer simulations have recently contributed in characterizing some key rare and transient events in CDKs, such as the reaction transition state and activation loop movement. Although not yet fully defined, we can now portray the enzymatic mechanism and plasticity of CDKs at high spatial and temporal resolution. These theoretical studies bridge with experiments and highlight structural determinants that could help in designing specific CDK inhibitors. © 2011 Future Science Ltd.

D'Abramo M.,University of Barcelona | D'Abramo M.,Computational Biophysics Group | Orozco M.,University of Barcelona | Amadei A.,University of Rome Tor Vergata
Chemical Communications | Year: 2011

Influence of external electric field as well as base substitution effects on the reduction/oxidation free energies of single stranded DNA suggest that base sequencing via measuring redox properties might be feasible under the conditions that (i) a difference of ∼ 230 kJ mol-1 in the oxidation potentials is enough to discriminate between nucleobases conductance signals and (ii) the strand is long enough to reduce end effects. © 2011 The Royal Society of Chemistry.

Zenn R.K.,University of Stuttgart | Abad E.,University of Stuttgart | Abad E.,Computational Biophysics Group | Kastner J.,University of Stuttgart
Journal of Physical Chemistry B | Year: 2015

The flavin-containing enzyme monoamine oxidase (MAO) is essential for the enzymatic decomposition of amine neurotransmitters. The exact mechanism of the oxidative deamination of amines to aldehydes by the enzyme has not yet been fully understood despite extensive research on the area. The rate limiting step is the reductive half-reaction where the Hα together with two electrons of the amine substrate is transferred to the flavin cofactor. However, it is still not known whether the hydrogen is transferred as a proton or a hydride. Experimental results cannot be fully explained by either of those mechanisms. In our previous work, theoretical results based on QM/MM calculations of the full enzyme show an intermediate situation between these two cases. In this paper, we report on an in-depth computational analysis concerning the role of the enzymatic environment for the reaction mechanism of human MAO-B with different p-substituted benzylamines as substrates. Our results show that steric and electrostatic effects from the active site environment turn the mechanism closer to an asynchronous polar nucleophilic mechanism. We found indications that the protein environment of MAO-A enhances the polar nucleophilic character of the mechanism compared to that of MAO-B. © 2015 American Chemical Society.

Bono F.,Sanofi S.A. | De Smet F.,Catholic University of Leuven | De Smet F.,Vesalius Research Center | Herbert C.,Sanofi S.A. | And 66 more authors.
Cancer Cell | Year: 2013

Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment. © 2013 Elsevier Inc.

Kappel C.,Theoretical and Computational Biophysics | Dolker N.,Theoretical and Computational Biophysics | Dolker N.,Computational Biophysics Group | Kumar R.,Theoretical and Computational Biophysics | And 5 more authors.
Physical Review Letters | Year: 2012

Experimental and computational dynamic force spectroscopy is widely used to determine the mechanical properties of single biomolecules. Whereas so far the focus has mainly been on rupture or unfolding forces, recent force-probe molecular dynamics simulations have revealed a strong loading rate dependence of biomolecular elasticities, which cannot be explained by the established one-dimensional transition-state treatments. We show that this nonequilibrium behavior can be explained by a theory that includes relaxation effects. For three structurally and mechanically quite diverse systems, a single relaxation mode suffices to quantitatively describe their loading-rate-dependent elastic behavior. Atomistic simulations of these systems revealed the microscopic nature of the respective relaxation modes. This result suggests a new type of "elasticity spectroscopy" experiment, which should render nonequilibrium properties of structured macromolecules accessible to single-molecule force spectroscopy. © 2012 American Physical Society.

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