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A Carboxylate to Amide Substitution That Switches Protein Folds
Author(s) -
Gianni Stefano,
McCully Michelle E.,
Malagrinò Francesca,
Bonetti Daniela,
De Simone Alfonso,
Brunori Maurizio,
Daggett Valerie
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201807723
Subject(s) - native state , chemistry , protein folding , biomolecule , protein engineering , folding (dsp implementation) , amide , intramolecular force , protein structure , amino acid , topology (electrical circuits) , stereochemistry , crystallography , biochemistry , mathematics , enzyme , combinatorics , electrical engineering , engineering
Metamorphic proteins are biomolecules prone to adopting alternative conformations. Because of this feature, they represent ideal systems to investigate the general rules allowing primary structure to dictate protein topology. A comparative molecular dynamics study was performed on the denatured states of two proteins, sharing nearly identical amino‐acid sequences (88 %) but different topologies, namely an all‐α‐helical bundle protein named G A 88 and an α+β‐protein named G B 88. The analysis allowed successful design of and experimental validation of a site‐directed mutant that promotes, at least in part, the switch in folding from G B 88 to G A 88. The mutated position, in which a glutamic acid was replaced by a glutamine, does not make any intramolecular interactions in the native state of G A 88, such that its stabilization can be explained by considering the effects on the denatured state. The results represent a direct demonstration of the role of the denatured state in sculpting native structure.