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Evaluation of ?-Amino Acid Replacements in Protein Loops: Effects on Conformational Stability and Structure.

ABSTRACT: ?-Amino acids have a backbone that is expanded by one carbon atom relative to ?-amino acids, and ? residues have been investigated as subunits in protein-like molecules that adopt discrete and predictable conformations. Two classes of ? residue have been widely explored in the context of generating ?-helix-like conformations: ?3 -amino acids, which are homologous to ?-amino acids and bear a side chain on the backbone carbon adjacent to nitrogen, and residues constrained by a five-membered ring, such the one derived from trans-2-aminocyclopentanecarboxylic acid (ACPC). Substitution of ? residues with their ?3 ?homologues within an ?-helix-forming sequence generally causes a decrease in conformational stability. Use of a ring-constrained ? residue, however, can offset the destabilizing effect of ??? substitution. Here we extend the study of ??? substitutions, involving both ?3 and ACPC residues, to short loops within a small tertiary motif. We start from previously reported variants of the Pin1 WW domain that contain a two-, three-, or four-residue ?-hairpin loop, and we evaluate ??? replacements at each loop position for each variant. By referral to the ?,? angles of the native structure, one can choose a stereochemically appropriate ACPC residue. Use of such logically chosen ACPC residues enhances conformational stability in several cases. Crystal structures of three ?-containing Pin1 WW domain variants show that a native-like tertiary structure is maintained in each case.

SUBMITTER: Mortenson DE

PROVIDER: S-EPMC5944345 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Evaluation of β-Amino Acid Replacements in Protein Loops: Effects on Conformational Stability and Structure.

Mortenson David E DE Kreitler Dale F DF Thomas Nicole C NC Guzei Ilia A IA Gellman Samuel H SH Forest Katrina T KT

Chembiochem : a European journal of chemical biology 20180213 6

β-Amino acids have a backbone that is expanded by one carbon atom relative to α-amino acids, and β residues have been investigated as subunits in protein-like molecules that adopt discrete and predictable conformations. Two classes of β residue have been widely explored in the context of generating α-helix-like conformations: β<sup>3</sup> -amino acids, which are homologous to α-amino acids and bear a side chain on the backbone carbon adjacent to nitrogen, and residues constrained by a five-memb ...[more]

PMID: 29272560

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Project description:Prediction of protein secondary structure from FTIR spectra usually relies on the absorbance in the amide I-amide II region of the spectrum. It assumes that the absorbance in this spectral region, i.e., roughly 1700-1500 cm-1 is solely arising from amide contributions. Yet, it is accepted that, on the average, about 20% of the absorbance is due to amino acid side chains. The present paper evaluates the contribution of amino acid side chains in this spectral region and the potential to improve secondary structure prediction after correcting for their contribution. We show that the β-sheet content prediction is improved upon subtraction of amino acid side chain contributions in the amide I-amide II spectral range. Improvement is relatively important, for instance, the error of prediction of β-sheet content decreases from 5.42 to 4.97% when evaluated by ascending stepwise regression. Other methods tested such as partial least square regression and support vector machine have also improved accuracy for β-sheet content evaluation. The other structures such as α-helix do not significantly benefit from side chain contribution subtraction, in some cases prediction is even degraded. We show that co-linearity between secondary structure content and amino acid composition is not a main limitation for improving secondary structure prediction. We also show that, even though based on different criteria, secondary structures defined by DSSP and XTLSSTR both arrive at the same conclusion: only the β-sheet structure clearly benefits from side chain subtraction. It must be concluded that side chain contribution subtraction benefit for the evaluation of other secondary structure contents is limited by the very rough description of side chain absorbance which does not take into account the variations related to their environment. The study was performed on a large protein set. To deal with the large number of proteins present, we worked on protein microarrays deposited on BaF2 slides and FTIR spectra were acquired with an imaging system.

Dataset Information

Evaluation of ?-Amino Acid Replacements in Protein Loops: Effects on Conformational Stability and Structure.

Publications

Evaluation of β-Amino Acid Replacements in Protein Loops: Effects on Conformational Stability and Structure.

Similar Datasets

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