Testing beta-helix terminal coils stability by targeted substitutions with non-proteogenic amino acids: a molecular dynamics study.

Departament d'Enginyeria Química, E. T. S. d'Enginyeria Industrial de Barcelona, Universitat Politècnica de Catalunya, Diagonal 647, Barcelona E-08028, Spain. david.zanuy@upc.edu

The search for new building block templates useful for nanostructures design, targets protein motifs with a wide range of structures. Stabilizing these building blocks when extracted from their natural environment becomes a fundamental goal in order to successfully control their assembly. Targeted replacements of natural residues by conformationally constrained amino acids were shown to be a successful strategy to achieve such stabilization. In this work, the effect of replacing natural amino acids by non-proteogenic residues in a beta-helix building block has been evaluated using extensive molecular dynamics simulations. Here, we focus on systematic substitutions of valine residues present in beta-sheet segments of a beta-helical building block excised from Escherichia coli galactoside acetyltransferase, residues 131-165. Four different types of non-proteogenic amino acids have been considered for substitution: (i) one dehydroamino acid, (ii) two d-amino acids, (iii) one beta-amino acid and (iv) two alpha,alpha-dialkylamino acids. Our results indicate that the ability of non-proteogenic amino acids to stabilize small building block motifs is site-dependent. We conclude that if the replacement does not alter the energy balance between attractive non-covalent interactions and steric hindrance, synthetic residues are suitable candidates to nucleate beta-helix formation.

PMID: 17897839 [PubMed - indexed for MEDLINE]