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Determining rates of energy transfer across non-covalent contacts for different states of a protein can provide information about dynamic and associated entropy changes during transitions between states. We investigate the relationship between rates of energy transfer across polar and nonpolar contacts and contact dynamics for the β 2 -adrenergic receptor, a rhodopsin-like G-protein coupled receptor, in an antagonist-bound inactive state and agonist-bound active state. From structures sampled during molecular dynamics (MD) simulations, we find the active state to have, on average, a lower packing density, corresponding to generally more flexibility and greater entropy than the inactive state. Energy exchange networks (EENs) are computed for the inactive and active states from the results of the MD simulations. From the EENs, changes in the rates of energy transfer across polar and nonpolar contacts are found for contacts that remain largely intact during activation. Change in dynamics of the contact, and entropy associated with the dynamics, can be estimated from the change in rates of energy transfer across the contacts. Measurement of change in the rates of energy transfer before and after the transition between states thereby provides information about dynamic contributions to activation and allostery.
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Computational studies of the principle of dynamic-change-driven protein interactions
Dynamic allostery emphasizes a role of entropy change manifested as a sole change in protein fluctuations without structural changes. This kind of entropy-driven effect remains largely understudied. The most significant examples involve protein-ligand interactions, leaving protein-protein interactions, which are critical in signaling and other cellular events, largely unexplored. Here we study an example of how protein-protein interaction (binding of Ras to the Ras binding domain [RBD] of the effector protein Raf) affects a subsequent protein association process (Ras dimerization) by quenching Ras internal motions through dynamic allostery. We also investigate the influence of point mutations or ambient temperature, respectively, on the protein dynamics and interaction of two other systems: in adenylate kinase (ADK) and in the EphA2 SAM:Ship2 SAM complex. Based on these examples, we postulate that there are different ways in which dynamic-change-driven protein interactions are manifested and that it is likely a general biological phenomenon.
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- Award ID(s):
- 2121426
- PAR ID:
- 10343946
- Date Published:
- Journal Name:
- Structure
- Volume:
- 30
- Issue:
- 6
- ISSN:
- 2688-903X
- Page Range / eLocation ID:
- 909 - 916
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/doi.org/10.1016/j.str.2022.03.008
