Abstract:
:Mutations in the hydrophobic interior of proteins are generally thought to weaken the interactions only in their immediate neighborhood. This forms the basis of protein engineering-based studies of folding mechanism and function. However, mutational work on diverse proteins has shown that distant residues are thermodynamically coupled, with the network of interactions within the protein acting as signal conduits, thus raising an intriguing paradox. Are mutational effects localized, and if not, is there a general rule for the extent of percolation and the functional form of this propagation? We explore these questions from multiple perspectives in this work. Perturbation analysis of interaction networks within proteins and microsecond long molecular dynamics simulations of several aliphatic mutants of ubiquitin reveal strong evidence of the distinct alteration of distal residue-residue communication networks. We find that mutational effects consistently propagate into the second shell of the altered site (even up to 15-20 Å) in proportion to the perturbation magnitude and dissipate exponentially with a decay distance constant of ∼4-5 Å. We also report evidence for this phenomenon from published experimental nuclear magnetic resonance data that strikingly resemble predictions from network theory and molecular dynamics simulations. Reformulating these observations onto a statistical mechanical model, we reproduce the stability changes of 375 mutations from 19 single-domain proteins. Our work thus reveals a robust energy dissipation-cum-signaling mechanism in the interaction network within proteins, quantifies the partitioning of destabilization energetics around the mutation neighborhood, and presents a simple theoretical framework for modeling the allosteric effects of point mutations.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Rajasekaran N,Suresh S,Gopi S,Raman K,Naganathan ANdoi
10.1021/acs.biochem.6b00798subject
Has Abstractpub_date
2017-01-10 00:00:00pages
294-305issue
1eissn
0006-2960issn
1520-4995journal_volume
56pub_type
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