Allosteric Effect Driven by Dynamics and Entropy
Paulo Mascarello Bisch1, David Perahia2 and Pedro Vitor Renault de Barros1,2
1Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil (email:pmbisch@biof.ufrj.br)
2Ecole Normale Supérieure de Cachan, France
Mercredi 24 Octobre 2018, 11h00
bibliothèque LCT, tour 12 - 13, 4ème étage
Allostery is a process by which binding of a molecule to one site alters the activity of an enzime at another site; it is a common and efficient strategy to control their activity. Classical models consider that allostery is associated to large conformational changes, but it occurs also in absence of significant rearrangements. The ligand-induced modulation of vibration modes of a protein could be at the origin of allosteric effect and entropy would be the main component of free energy variations. We adopt a theoretical approach based on vibrational normal mode analysis within a simple harmonic model to put forward the role of dynamics and entropic effects. We present an investigation on allostery in cysteine proteases from the Papain family, including cathepsins from Trypanosoma protozoa, causatives of important tropical diseases, like Chagas disease and African sleeping sickness. Using a set of computational and theoretical methods, we investigate possible allosteric sites and the role of some ligands in the regulation of the activity of these cathepsins. The understanding about dynamic and allostery of these targets could help the rational design of new drugs, particularly important perspective since allosteric drugs could be more specific, efficient and cause less side effects.