The role of slow and fast protein motions in allosteric interactions

Abstract

Allostery is fundamentally thermodynamic in nature. Long-range communication in proteins may be mediated not only by changes in the mean conformation with enthalpic contribution but also by changes in dynamic fluctuations with entropic contribution. The important role of protein motions in mediating allosteric interactions has been established by NMR spectroscopy. By using CAP as a model system, we have shown how changes in protein structure and internal dynamics can allosterically regulate protein function and activity. The results indicate that changes in conformational entropy can give rise to binding enhancement, binding inhibition, or have no effect in the expected affinity, depending on the magnitude and sign of enthalpy-entropy compensation. Moreover, allosteric interactions can be regulated by the modulation a lowpopulated conformation states that serve as on-pathway intermediates for ligand binding. Taken together, the interplay between fast internal motions, which are intimately related to conformational entropy, and slow internal motions, which are related to poorly populated conformational states, can regulate protein activity in a way that cannot be predicted on the basis of the protein's ground-state structure.

Transient association between proteins elicits alteration of dynamics at sites far away from interfaces

“…However, in recent years the definition of allostery has been broadened by including the alteration in nature and extent of dynamics at sites away from the site of perturbation, and few proteins have been reported to show such dynamic allostery (Arumugam et al, 2003;Fayos et al, 2003;Gr€ unberg et al, 2006;Louet et al, 2015;Popovych et al, 2006). Allostery is achieved through altered entropy of the protein side chain or backbone (and/or other entropic effects) (Popovych et al, 2006;Tzeng and Kalodimos, 2015). Furthermore, it has been proposed that large-scale motions associated with proteins are important carriers of allosteric signals without requiring a conformational change (Rodgers et al, 2013).…”

Millisecond Timescale Motions Connect Amino Acid Interaction Networks in Alpha Tryptophan Synthase

“…These results suggest networks in proteins (at least those identified by CHESCA) do not simply reflect structural interactions in the lowest energy, ground-state conformation, but rather these networks also reflect motional coupling and/or interactions as proteins fluctuate into higher energy protein conformations. This network view is more complex than the “mechanical linkage” model (Yu and Koshland, 2001 ) in which allosteric signals propagate through sequential structural changes in a “domino-like” fashion, and is more compatible with dynamically driven allostery (Cooper and Dryden, 1984 ; Reinhart et al, 1989 ; Petit et al, 2009 ; Motlagh et al, 2014 ; Kornev and Taylor, 2015 ; Nussinov and Tsai, 2015 ; Tzeng and Kalodimos, 2015 ; Guo and Zhou, 2016 ; Saavedra et al, 2018 ).…”

“…In these systems, allosteric effectors may change structural dynamics or conformational sampling to affect interactions with other molecules. In this “dynamically driven allostery” (Cooper and Dryden, 1984 ; Reinhart et al, 1989 ; Petit et al, 2009 ; Motlagh et al, 2014 ; Kornev and Taylor, 2015 ; Nussinov and Tsai, 2015 ; Tzeng and Kalodimos, 2015 ; Guo and Zhou, 2016 ; Saavedra et al, 2018 ), key residues may still guide changes to protein structural dynamics (Rodgers et al, 2013 ; McLeish et al, 2015 ; Capdevila et al, 2017 ).…”

Site‐directed spin label electron paramagnetic resonance spectroscopy as a probe of conformational dynamics in the Fe(III) “locked‐off” state of the CO‐sensing transcription factor CooA

“…Unlike CRP, CooA regulates anaerobic carbon monoxide (CO) metabolism in facultative and obligate anaerobes in response to CO . Although a structural mechanism for the allosteric activation of CooA exists, the role of dynamics, which has been shown to be critical in regulating function in CRP, has not been explored for CooA . In order to compare the role of dynamics in allosteric activation between CooA and CRP, we developed a means to probe conformational dynamics in CooA and demonstrated that CooA samples multiple conformations in the poorly characterized Fe(III) “ locked‐off ” state.…”