Modulation of allosteric coupling by mutations: from protein dynamics and packing to altered native ensembles and function

Abstract

A large body of work has gone into understanding the effect of mutations on protein structure and function. Conventional treatments have involved quantifying the change in stability, activity and relaxation rates of the mutants with respect to the wild-type protein. However, it is now becoming increasingly apparent that mutational perturbations consistently modulate the packing and dynamics of a significant fraction of protein residues, even those that are located >10–15 Å from the mutated site. Such long-range modulation of protein features can distinctly tune protein stability and the native conformational ensemble contributing to allosteric modulation of function. In this review, I summarize a series of experimental and computational observations that highlight the incredibly pliable nature of proteins and their response to mutational perturbations manifested via the intra-protein interaction network. I highlight how an intimate understanding of mutational effects could pave the way for integrating stability, folding, cooperativity and even allostery within a single physical framework.

Stability and dynamics interrelations in a Lipase: Mutational and MD simulations based investigations

“…In the case of CM2, the mutation site is near the site of altered dynamics whereas in case of CM1, CM3 and CM4 these are far away in space. Such an observation, though compelling, is not out of line with the literature (40,(51)(52)(53). Such long distance effect is speculated to be through coordinated motion in protein or through alteration of hydrogen bond networks.…”

Dancing Molecules: Rewiring Cooperative Communications within 14-3-3 ζ Docking Proteins

“…[4] Whereby, any perturbation from mutation would involve reorganization of evolutionarily tuned interaction networks. [7] Such mutations occur in disease states resulting in a redistribution of the ensemble to favor the "ON" state rendering the molecule constitutively active. [4] Due to the role of 14-3-3 ζ in neurodegenerative disease [12] and cancer [39,40] , the ability to rewire allosteric interactions without disrupting evolutionarily tuned interaction networks would allow for novel drug discovery.…”

“…As the protein core promotes a range of ensembles governed by specific packing interactions. 7] Thusly, any perturbation from mutation within the protein's core would involve reorganization of the evolutionarily tuned interaction network. [7] Results of mutations are manifested in disease states, where ensembles are redistributed to favor the "ON" state rendering the protein constitutively active.…”

“…7] Thusly, any perturbation from mutation within the protein's core would involve reorganization of the evolutionarily tuned interaction network. [7] Results of mutations are manifested in disease states, where ensembles are redistributed to favor the "ON" state rendering the protein constitutively active. [4] 14-3-3 docking proteins are key regulators that have been reported to interact with over 300 protein binding partners and that effect multiple signaling pathways.…”

“…Whereby, aberrant mutation may result in abrupt reorganization of the interaction network. [7] The ability to rewire cooperative communications in 14-3-3 ζ without disrupting natively evolved ensembles would allow altering of cellular pathways. This is significant as 14-3-3 ζ has been associated with neurodegenerative disease and cancer [12] as well as diseases such as glaucoma via the RhoA signaling pathway [43] .…”