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Abstract:

Intrinsically disordered proteins (IDPs) are a set of proteins that lack a definite secondary structure in solution. IDPs can acquire tertiary structure when bound to their partners; therefore, the recognition process must also involve protein folding. The nature of the transition state (TS), structured or unstructured, determines the binding mechanism. The characterization of the TS has become a major challenge for experimental techniques and molecular simulations approaches since diffusion, recognition, and binding is coupled to folding. In this work we present atomistic molecular dynamics (MD) simulations that sample the free energy surface of the coupled folding and binding of the transcription factor c-myb to the cotranscription factor CREB binding protein (CBP). This process has been recently studied and became a model to study IDPs. Despite the plethora of available information, we still do not know how c-myb binds to CBP. We performed a set of atomistic biased MD simulations running a total of 15.6 μs. Our results show that c-myb folds very fast upon binding to CBP with no unique pathway for binding. The process can proceed through both structured or unstructured TS's with similar probabilities. This finding reconciles previous seemingly different experimental results. We also performed Go-type coarse-grained MD of several structured and unstructured models that indicate that coupled folding and binding follows a native contact mechanism. To the best of our knowledge, this is the first atomistic MD simulation that samples the free energy surface of the coupled folding and binding processes of IDPs. © 2016 American Chemical Society.

Registro:

Documento: Artículo
Título:Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations
Autor:Ithuralde, R.E.; Roitberg, A.E.; Turjanski, A.G.
Filiación:Departamento de Química Biológica, Analítica y Química Física, Facultad de Ciencias Exactas y Naturales, IQUIBICEN/INQUIMAE-UBA/CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Intendente Güiraldes 2160, Pabellón II, Buenos Aires, C1428EGA, Argentina
Department of Chemistry, University of Florida, PO Box 117200, Gainesville, FL 32611-7200, United States
Palabras clave:Bins; Free energy; Molecular dynamics; Proteins; Technology transfer; Atomistic molecular dynamics; Atomistic simulations; CREB binding proteins; Experimental techniques; Free energy surface; Intrinsically disordered proteins; Molecular simulations; Secondary structures; Binding energy; amino acid; cyclic AMP responsive element binding protein binding protein; intrinsically disordered protein; protein c Myb; tryptophan; Article; binding kinetics; hinge region; hydrophobicity; mean residence time; molecular dynamics; nuclear magnetic resonance; protein binding; protein conformation; protein folding; protein protein interaction; protein secondary structure; surface property
Año:2016
Volumen:138
Número:28
Página de inicio:8742
Página de fin:8751
DOI: http://dx.doi.org/10.1021/jacs.6b02016
Título revista:Journal of the American Chemical Society
Título revista abreviado:J. Am. Chem. Soc.
ISSN:00027863
CODEN:JACSA
CAS:amino acid, 65072-01-7; cyclic AMP responsive element binding protein binding protein, 190209-80-4; tryptophan, 6912-86-3, 73-22-3
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v138_n28_p8742_Ithuralde

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Citas:

---------- APA ----------
Ithuralde, R.E., Roitberg, A.E. & Turjanski, A.G. (2016) . Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations. Journal of the American Chemical Society, 138(28), 8742-8751.
http://dx.doi.org/10.1021/jacs.6b02016
---------- CHICAGO ----------
Ithuralde, R.E., Roitberg, A.E., Turjanski, A.G. "Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations" . Journal of the American Chemical Society 138, no. 28 (2016) : 8742-8751.
http://dx.doi.org/10.1021/jacs.6b02016
---------- MLA ----------
Ithuralde, R.E., Roitberg, A.E., Turjanski, A.G. "Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations" . Journal of the American Chemical Society, vol. 138, no. 28, 2016, pp. 8742-8751.
http://dx.doi.org/10.1021/jacs.6b02016
---------- VANCOUVER ----------
Ithuralde, R.E., Roitberg, A.E., Turjanski, A.G. Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations. J. Am. Chem. Soc. 2016;138(28):8742-8751.
http://dx.doi.org/10.1021/jacs.6b02016