Abstract
BackgroundThe mechanisms underlying protein function and associated conformational change are dominated by a series of local entropy fluctuations affecting the global structure yet are mediated by only a few key residues. Transitional Dynamic Analysis (TDA) is a new method to detect these changes in local protein flexibility between different conformations arising from, for example, ligand binding. Additionally, Positional Impact Vertex for Entropy Transfer (PIVET) uses TDA to identify important residue contact changes that have a large impact on global fluctuation. We demonstrate the utility of these methods for Cyclin-dependent kinase 2 (CDK2), a system with crystal structures of this protein in multiple functionally relevant conformations and experimental data revealing the importance of local fluctuation changes for protein function.ResultsTDA and PIVET successfully identified select residues that are responsible for conformation specific regional fluctuation in the activation cycle of Cyclin Dependent Kinase 2 (CDK2). The detected local changes in protein flexibility have been experimentally confirmed to be essential for the regulation and function of the kinase. The methodologies also highlighted possible errors in previous molecular dynamic simulations that need to be resolved in order to understand this key player in cell cycle regulation. Finally, the use of entropy compensation as a possible allosteric mechanism for protein function is reported for CDK2.ConclusionThe methodologies embodied in TDA and PIVET provide a quick approach to identify local fluctuation change important for protein function and residue contacts that contributes to these changes. Further, these approaches can be used to check for possible errors in protein dynamic simulations and have the potential to facilitate a better understanding of the contribution of entropy to protein allostery and function.
Highlights
The mechanisms underlying protein function and associated conformational change are dominated by a series of local entropy fluctuations affecting the global structure yet are mediated by only a few key residues
Transitional Dynamic Analysis conducted on the Cyclin-dependent kinase 2 (CDK2) activation cycle TDA and Positional Impact Vertex for Entropy Transfer (PIVET) are algorithms designed to identify significant changes in protein fluctuations as modeled by the Gaussian Network Model (GNM)[24]
Have protein architectures and functional residues evolved to take advantage of fluctuation changes? Structural constraints inherently impose a certain amount of evolutionary pressure on sequences [41,42,43] and we propose that the dynamic restraints needed for function contribute to this selection and can be identified using TDA
Summary
The mechanisms underlying protein function and associated conformational change are dominated by a series of local entropy fluctuations affecting the global structure yet are mediated by only a few key residues. It has been found that a select set of key residues has a large impact on conformational preference With this expanded view of allostery, the model allows for the consideration of other contributing factors and possible mechanisms such as entropy that was initially proposed by the Cooper-Dryden model[7]. This model states that, in an extreme case, the allosteric nature of proteins can be achieved though a shift in vibrational modes without a conformational change in structure. The same phenomenon is observed during ligand binding to dihydrofolate reductase as modeled by COREX[4]
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