Simulated Evolution of Emergent Chiral Structures in Polyalanine

Abstract

The relationship between monomer chirality and polymer structure has been studied using both theoretical and experimental methods. Atomistic models, such as the ones employed in computational protein folding and design, can be used to study the relationship between monomer chirality and the properties of polypeptides. Using a simulated evolution approach that combines side-chain epimerization with backbone flexibility, we recapitulate the relationship between basic forces that drive secondary structure formation and sequence homochirality. Additionally, we find heterochiral motifs including a C-terminal helix capping interaction and stable helix-reversals that result in bent helix structures. Our studies show that simulated evolution of chirality with backbone flexibility can be a powerful tool in the design of novel heteropolymers with tuned stereochemical properties.

Designing artificial enzymes by intuition and computation

“…Computational studies of foldamers are still in their infancy. Several groups have used simulation approaches to study the conformational space available to peptidomimetics incorporating D-amino acids 104, 105 or β-amino acids 106, 107 , as well as completely non-biological foldamers such as m -phenylene ethylenes (mPE) 108 . These studies establish non-natural scaffolds which can then be functionalized to facilitate reactivity.…”

Diabetes Mellitus due to Misfolding of a β-Cell Transcription Factor: Stereospecific Frustration of a Schellman Motif in HNF-1α

“…In addition, the positive ϕ angle of G20 would be unfavorable for an L-amino acid (ΔΔG u ca −1 kcal/mol). 31 Whereas wild-type HNF-p1w is soluble as a monodisperse dimer at high peptide concentrations, the G20R analogue exhibits poor solubility. This was circumvented as in previous studies 16 by use of a charged C-terminal extension (comprising residues KEK of the extended polypeptide; Supplementary Data).…”

Computational Design of Thermostabilizingd-Amino Acid Substitutions

“…The potential for such interactions were noted in Monte Carlo simulations of poly- ld -alanine peptides, sampling both backbone flexibility and side chain chirality. 21 In simulations of an eleven residue poly-alanine peptide, ( l- Ala) 9 - d- Ala- l- Ala and ( d- Ala) 9 - l -Ala- d -Ala were frequently found. These corresponded to right and left-handed α-helices respectively.…”