INQUIMAE   12526
INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
All-atom simulation of the folding and binding of an intrinsically disordered protein
Autor/es:
ITHURALDE, RAÚL ESTEBAN; ROITBERG, ADRIÁN; TURJANSKI, ADRIÁN
Lugar:
Denver
Reunión:
Congreso; 249th American Chemical Society National Meeting & Exposition; 2015
Institución organizadora:
American Chemical Society
Resumen:
Intrinsically Disordered Proteins (IDPs) comprise a wide set of proteins or protein domains that lack a definite secondary structure in solution and sample many different configurations. IDPs may acquire some structure when bound to their partners and thus the binding process needs the folding of the protein, that could follow a conformational selection mechanism, an induced fit one or a combination of both. c-Myb is a transcription factor involved in the regulation of hemapoietic cells life cycle. The TAD region of c-Myb is intrinsically disordered (retains approximately of 30% of helicity in solution) and folds upon binding to the KIX domain of CBP[1] The NMR structure of the complex has been solved showing that cMyb forms an α-helix structure, with a kink in Leu302, which allows this residue to be deeply buried in a hydrophobic groove between KIX α1 and α3[4] Kinetic studies of cMyb - KIX binding are consistent with a two-state, one step process, with no accumulation of intermediates. [1,2]. The association process has an apparent activation energy of approximately 11 kcal/mol. Previous experimental Phi value analysis was done on TAD-c-Myb and the results are consistent with a quite ordered transition state, in contradiction with other studies that show that prefolding of c-Myb does not increase kon [2,3]. We performed all atom biased molecular dynamics simulations running a total of 16us in implicit solvent. Our results show that c-Myb folds incredibly fast upon binding to KIX and that pre-folded configurations of c-Myb can also bind with a similar activation barrier. The transition state has a broad configuration, with helicity going from 30% to 70%. The calculated activation energies agree with fluorescence experiments [1]. We show that the fast folding upon binding of the unstructured c-Myb preclude previous fluorescent experiments to differentiate between mechanisms. Both all atom and Go-type simulations show similar results, indicating that folding upon binding follows a native contact mechanism similarly to previous folding simulations of globular protein[5] To the best of our knowledge this is the first work to provide an atomistic understanding of the free energy surface of the binding process of IDPs.
rds']