Influence of hydrophobic interactions on the conformational adaptability of the β‐Ala residue

Abstract

The chemical synthesis and X-ray crystal structure analysis of a model peptide incorporating a conformationally flexible beta-Ala residue: Boc-beta-Ala-Pda, 1 (C23H46N2O3: molecular weight = 398.62) have been described. The peptide crystallized in the crystal system triclinic with space group P21: a = 5.116(3) A, b = 5.6770(10) A, c = 21.744(5) A; alpha = 87.45 degrees, beta = 86.87 degrees, gamma = 90.0 degrees; Z = 1. An attractive feature of the crystal molecular structure of 1 is the induction of a reasonably extended backbone conformation of the beta-Ala moiety, i.e. the torsion angles phi approximately -115 degrees, mu approximately 173 degrees and psi approximately 122 degrees, correspond to skew-, trans and skew+ conformation, respectively, by an unbranched hydrophobic alkyl chain, Pda, which prefers an all-anti orientation (theta1 approximately -153 degrees, theta2 approximately ellipsis theta14 approximately +/-178 degrees ). The observation is remarkable because, systematic conformational investigations of short linear beta-Ala peptides of the type Boc-beta-Ala-Xaa-OCH3 (Xaa = Aib or Acc6) have shown that the chemical and stereochemical characters of the neighboring moieties may be critical in dictating the overall folded and/or unfolded conformational features of the beta-Ala residue. The overall conformation of 1 is typical of a 'bar'. It appears convincing that, in addition to a number of hydrophobic contacts between the parallel arranged molecules, an array of conventional N-HellipsisO=C intermolecular H-bonding interactions stabilize the crystal molecular structure. Moreover, the resulting 14-membered pseudo-ring motif, generated by the amide-amide interactions between the adjacent molecules, is completely devoid of nonconventional C-HellipsisO interaction. The potentials of the conformational adaptation of the beta-Ala residue, to influence and stabilize different structural characteristics have been highlighted.

Unusual Folding Propensity of an Unsubstituted β,γ‐Hybrid Model Peptide: Importance of the CH⋅⋅⋅O Intramolecular Hydrogen Bond

“…There exists a more complex network of weaker apolar interactions [7c, 15] vis-à-vis hydrophobic and/or van der Waals contacts between symmetry related molecules belonging to adjacent rows. As recognised previously, [15] the effectual C···C distances in 2 also ranged between approximately 3.80-4.20 (Table 4). As recognised previously, [15] the effectual C···C distances in 2 also ranged between approximately 3.80-4.20 (Table 4).…”

“…Figure 6 illustrates numerous C···C short contacts between Boc groups and methylene units of b-Ala and g-Abu. As recognised previously, [15] the effectual C···C distances in 2 also ranged between approximately 3.80-4.20 (Table 4). However, there exists little experimental information concerning the distance dependent effectiveness of such hydrophobic contacts.…”

Novel α-MSH Peptide Analogues with Broad Spectrum Antimicrobial Activity

“…The amphipathic helical structure along residues 8–13 is likely responsible for the superior antimicrobial activity of the substituted peptides whereas the partial lack of helicity in DNal probably contributes to its reduced activity. Indeed, the residues Deg [26], tButGly [27], Ac3c [36], β-Ala [31], and Acpc [32], which do not stabilize regular right handed helices, did not promote activity in the corresponding peptides.Therefore, consistent with previous observations, the amphipathic helical content proved to be a key factor in the activity of antimicrobial peptides [37], [38].…”

“…Further, they show precise conformational preferences. In particular, the conformationally flexible noncoding β-alanine (β-Ala) residue shows two energetically preferred conformations: a folded conformation (μ∼±65±10°) and an extended conformation (μ∼±165±10°) that are easily accommodated in both acyclic and cyclic peptides where they determine the overall molecular structures [31]. The cyclic (1R,2R)-2-aminocyclopentane carboxylic acid (Acpc) is a more constrained -amino acid that determines a so called “12-helix” (a 12-membered ring hydrogen bonds) when inserted into a peptide sequence [32].…”

A combined extended and helical backbone for Boc‐(Ala‐Leu‐Ac7c‐)2‐OMe*

“…Except for the two values of 4.1 and 4.3 Å, there does not seem to be the kind of attraction that has been found for saturated hydrocarbon chains in other crystals, such as the many contacts with values of c . 4.23 Å between parallel hydrocarbon chains in crystals of Boc‐ β ‐Ala‐pentadecylamine (18) and C···C distances of 4.2–4.3 Å across the cavities of macrocycles related to cyclic Nylons (19).…”