The influence of solvent on conformational properties of peptides with Aib residue—a DFT study

J Mol Model (2017) 23:349 https://doi.org/10.1007/s00894-017-3508-4 ORIGINAL PAPER The influence of solvent on conformational properties of peptides with Aib residue—a DFT study Roksana Wałęsa 1 & Małgorzata A. Broda 1 Received: 8 June 2017 / Accepted: 24 October 2017 # The Author(s) 2017. This article is an open access publication Abstract The conformational propensities of the Aib residue on the example of two model peptides Ac-Aib-NHMe (1) and Ac-Aib-NMe2 (2), were studied by B3LYP and M06-2X functionals, in the gas phase and in the polar solvents. To verify the reliability of selected functionals, we also performed MP2 calculations for the tested molecules in vacuum. Polarizable continuum models (PCM and SMD) were used to estimate the solvent effect. Ramachandran maps were calculated to find all energy minima. Noncovalent intramolecular interactions due to hydrogen-bonds and dipole attractions between carbonyl groups are responsible for the relative stabilities of the conformers. In order to verify the theoretical results, the available conformations of similar X-ray structures from the Cambridge Crystallographic Data Center (CCDC) were analyzed. The results of the calculations show that both derivatives with the Aib residue in the gas phase prefer structures stabilized by intramolecular N–H⋯O hydrogen bonds, i.e., C5 and C7 conformations, while polar solvent promotes helical conformation with φ, ψ values equal to +/−60°, +/−40°. In addition, in the case of molecule 2, the helical conformation is the only one available in the polar environment. This result is fully consistent with the X-ray data. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00894-017-3508-4) contains supplementary material, which is available to authorized users. * Małgorzata A. Broda Roksana Wałęsa 1 Faculty of Chemistry, University of Opole, 48, Oleska St., 45-052 Opole, Poland Keywords α-Aminoisobutyric acid residue . N-methylation . Conformational analysis . Solvent effect . DFT calculations . X-ray crystallography Introduction Achiral α-aminoisobutyryl residue (Aib, α,α-dimethylglycine) is a common component in peptides produced by various microorganisms [1–4]. gem-Dimethyl substitution on the Cα-atom severely reduces the conformational freedom of this amino acid residue. Fungal peptides with proven antibiotic activity containing at least one α,α-dimethylglycine residue are called peptaibiotics [5]. Alamethicin and antyameobin [5] were the first examined and characterized peptaibiotics. Moreover, among known peptaibiotics are chlamydocin with cyclic backbone [4], zervamicin and emerimicin [6]. Since the Aib amino acid is not ribosomally encoded, peptides containing this residue are more resistant to proteolytic enzymes than peptides containing protein amino acids only. The Aib residue is used as a modifier of naturally occurring and biologically active peptides [7, 8] due to its unique structural features, introduced by the presence of two methyl groups at Cα. Analysis of peptide crystal structures shows that Aib residues favor the formation of 310- or α-helical structures. The type of helix depends strongly on peptide chain length and on the number of the Aib residues in the peptide. So, it is well recognized that tri-, tetra- and pentapeptides containing at least one Aib residue adopt mainly a 310 helix conformation. However, longer (6–20 residues) Aib-containing peptides fold predominantly, but not exclusively, into left- or right-handed α-helices [4, 5, 9]. The vibrational circular dichroism (VCD) and infre-red (IR) methods are especially reliable for discriminating 310- and α-helices [10]. α-Aminoisobutyric acid 349 J Mol Model (2017) 23:349 Page 2 of 12 homooligopeptides in the gas phase and solution were recently studied by Barone and coworkers [11–14] using an improved AMBER force field. In these studies, the solvent effect was shown as the critical factor governing the conformational behavior of a single Aib residue and in homooligopeptides. Molecular dynamics simulations show that the α-helix is the preferred structure in aqueous solution, while in DMSO the 310-helical structure is predominant. The α,α-dimethylglycine residue also shows a strong tendency, even stronger than that of proline [15], to promote βturn conformations. For Aib residues, β-turn conformations of type I, I′ and III, III’ are usually observed when this nonstandard amino acid residue is placed at both corners of turns. However, occurrence of the Aib residue at the i + 2 position results in a type II β-turn [15–19]. The peptide with the AibGly turn-initiating sequence shows a very stable β-hairpin conformation over a wide temperature range, as studied by isotope-edited IR spectroscopy and molecular modeling [20, 21]. The conformational properties of the Aib residue have been extensively studied theoretically. The conformational preferences of a model Ac-Aib-NHMe peptide containing the Aib residue were established for the first time in 1972 [22]. According to the latter authors, the α-aminoisobutyryl residue has a strong tendency to adopt helical conformations, and typical torsion angles φ, ψ for the Aib residue are −57° and −47°, respectively. Subsequent theoretical studies have confirmed these reports. Ramachandran maps calculated using the CFF91 force field indicated that this non-standard amino acid adopts an α-helical conformation in model diamide [23]. However, theoretical studies carried out in the gas phase using quantum-mechanical methods (HF, B3LYP and MP2) showed that the Aib residue has a tendency to adopt C5 and C7 conformations stabilized by intramolecular hydrogen bonds [24, 25]. Similarly, the potential energy surfaces (PES) calculated by the parm96 force field demonstrated that the most preferred structures of Ac-Aib-NHMe are also C5 and C7 conformers [26]. PCM/B3LYP/6–31 + G(d,p) calculations in solvent showed that the most stable structure in a water environment is the extended conformer C5, but the energy of the γ turn structure is only 1 kcal mol−1 higher [24]. The conformational properties of Ac-Aib-NMe2 diamide have not been studied as extensively as their non-methylated C-terminal amide bond analog. The potential energy surfaces were calculated using molecular mechanics methods [23]. These calculations show that the most stable conformation of this peptide is the α conformation with torsional angles of φ, ψ = 60° and 60°, respectively. As mentioned earlier, the use of non-standard residues such as Aib could be beneficial in enhancing the biological effects of natural or modified peptides. Another promising way to improve the pharmacological parameters of peptides is their modification by replacing the hydrogen atom of the amide bond by a methyl group—referred to as N-methylation. Introduction of a tertiary amide bond into the peptide chain results in a reduction in conformational freedom of the peptide due to steric hindrance (...truncated)