Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations
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), struct...
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2016
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paper:paper_00027863_v138_n28_p8742_Ithuralde2023-06-08T14:22:53Z Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations Ithuralde, Raul Esteban Turjanski, Adrián Gustavo 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 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. Fil:Ithuralde, R.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Turjanski, A.G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2016 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v138_n28_p8742_Ithuralde http://hdl.handle.net/20.500.12110/paper_00027863_v138_n28_p8742_Ithuralde |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Ithuralde, Raul Esteban Turjanski, Adrián Gustavo Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations |
| topic_facet |
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 |
| description |
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. |
| author |
Ithuralde, Raul Esteban Turjanski, Adrián Gustavo |
| author_facet |
Ithuralde, Raul Esteban Turjanski, Adrián Gustavo |
| author_sort |
Ithuralde, Raul Esteban |
| title |
Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations |
| title_short |
Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations |
| title_full |
Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations |
| title_fullStr |
Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations |
| title_full_unstemmed |
Structured and Unstructured Binding of an Intrinsically Disordered Protein as Revealed by Atomistic Simulations |
| title_sort |
structured and unstructured binding of an intrinsically disordered protein as revealed by atomistic simulations |
| publishDate |
2016 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v138_n28_p8742_Ithuralde http://hdl.handle.net/20.500.12110/paper_00027863_v138_n28_p8742_Ithuralde |
| work_keys_str_mv |
AT ithuralderaulesteban structuredandunstructuredbindingofanintrinsicallydisorderedproteinasrevealedbyatomisticsimulations AT turjanskiadriangustavo structuredandunstructuredbindingofanintrinsicallydisorderedproteinasrevealedbyatomisticsimulations |
| _version_ |
1768542528415465472 |