Designing amino acids to determine the local conformations of peptides.

Abstract

The local conformations of proteins and peptides are determined by the amino acid sequence. However, the 20 amino acids encoded by the genome allow the peptide backbone to fold Into many conformations, so that even for a smail peptide It becomes very difficult to predict the threedimensional structure. By using empirical conformational energy calculations a set of amino acids has been designed that would be expected to constrain the conformation of a peptide or a protein to one or two local minima. Most of these amino acids are based on asymmetric ubstItutions at the Ca atom of each residue. The HO atom of alanine was repad by various groups: -OCH3, -NCH3, -SCH3, -CONH2, -CONHCH3, -CON(CH3)2, -NH CO CH3, -phenyl, or -o-(OCH3)phenyl. Several of these new amino acids are pedt to fold into unique peptide conformations such as right-handed a-helical, left-handed a-helical, or extended. In an attempt to produce an amino acid that fvored the CV' conformation (torsion angles: * = -70 and # = +70%), an extra amide group was added to the CP atom of the asparagine side chain. Conformationally restried amino acids of this type could prove useful for developing new peptide pharmaceuticals, catalysts, or polymers.The prediction of the three-dimensional structures of peptides and proteins is not yet possible (1, 2). In part, the difficulties stem from the intrinsic conformational freedom associated with each amino acid in the polypeptide chain (3, 4). If we assume that the conformational freedom is determined essentially by the 4 and 4 rotations about the N-Ca and Cat-C' bonds, respectively, almost all ofthe amino acids except proline and glycine are able to access -30% of the two-dimensional (4, *) conformational space (5). Proline restricts the conformational freedom considerably (6), whereas glycine allows access to >60%6 of the total (4, @) rotational space (7). When additional degrees of freedom are considered (e.g., bond angle bending or bond length stretching), the accessible conformational space is even larger (8, 9). As a consequence, unless there are unusual amino acids in a peptide sequence (10,11) and/or the peptide is cyclic (12), most small peptides will have multiple conformations in solution. In proteins, long-range interactions lead to cooperative folding (13) and low-energy conformations which include structures such as f3-sheets and helices (a or 310).However, constraints on the local conformation of the polypeptide chain are relatively weak, thus predicting a priori that the preferred local conformation of a peptide requires an accurate comparison of the enormous numbers of possible conformations. Even the relatively simple task of redesigning peptide loops by homology modeling requires approximations that hinder the reliability of these calculations (2,14,15), and when there is no highly homologous structure, the semi-empirical calculations are not yet sufficiently powerful to generate a reliable model of the three-dimensional structure.Small peptides are ubiquitous regulators in many biological s...

Monitoring the structural consequences of Phe12→d‐Phe and Leu15→Aib substitution in human/rat corticotropin releasing hormone

“…w ¼ )34° [50]). According to these values, the Aib u torsion angle deviates less from a-than from 3 10 -helix typical values ()55.2°and )49.9°, respectively [48]) while the w torsion angle is practically the same as the ideal w-value ()34°) for 3 10 helical configurations ()52.2°for a-helix [48]).…”

“…This limitation is imposed by the steric hindrance that arises from its gem‐dimethyl group. The torsion angles for the main‐chain conformation of Aib15 in the family of 40 energy minimized structures are calculated as ϕ = −59.6° ± 1.5 and ψ = −31.9 ± 1.5, while for the mean energy minimized structure they are −56.5° and −31.0°, respectively, close to those of Aib conformational energy minima (ϕ = − 58° and ψ = −34°[50]). According to these values, the Aib ϕ torsion angle deviates less from α‐ than from 3 10 ‐helix typical values (−55.2° and −49.9°, respectively [48]) while the ψ torsion angle is practically the same as the ideal ψ‐value (−34°) for 3 10 helical configurations (−52.2° for α‐ helix [48]).…”

Enhanced Protein Thermostability by Ala → Aib Replacement

“…Moreover, Aib has been reported to possess a slightly higher intrinsic helical propensity than Ala, which is the most helix-favoring among the 20 protein amino acids ( , ). In this respect, theoretical studies have indicated that the helix-stabilizing effect of Aib is caused by the geminal methyl groups which severely reduce the allowed conformational space and restrict the peptide backbone torsion angles (φ, ψ) to those characteristic of the helical configuration ( 27 , − . Therefore, the incorporation of Aib into a polypeptide chain is expected to indirectly stabilize the folded structure by decreasing the chain entropy of the unfolded state.…”

Feleucin-K3 Analogue with an α-(4-Pentenyl)-Ala Substitution at the Key Site Has More Potent Antimicrobial and Antibiofilm Activities in Vitro and in Vivo

“…In addition, K59 is a quaternary carbon amino acid replacement analogue. Many studies have shown that the introduction of a quaternary carbon can improve the stability of peptides, − making them resistant to proteases. Our results showed that K59 has good stability for four types of bacteria in physiological salt environments and serum.…”