Intrinsic conformational characteristics of beta-peptides built up from simple achiral and chiral beta-amino acid residues (i.e., HCO-beta-Ala-NH2, HCO-beta-Abu-NH2) were studied using quantum chemical calculations and 1H-NMR spectroscopy. A conformer-based systematic and uniform nomenclature was introduced to differentiate conformers. Geometry optimizations were performed on all homoconformers of both HCO-(beta-Ala)(k)-NH2 and HCO-(beta-Abu)(k)-NH2 (1 < or = k < or = 6) model systems at the RHF/3-21G and RHF/6-311++G(d, p) levels of theory. To test for accuracy and precision, additional computations were carried out at several levels of theory [e.g., RHF/6-31G(d), and B3LYP/6-311++G(d, p)]. To display the folding preference, the relative stability of selected conformers as function of the length of the polypeptide chain was determined. Ab initio population distribution of hexapeptides and the conformational ensemble of synthetic models composed of beta-Ala and beta-Abu studied using 1H-NMR in different solvents were compared at a range of temperatures. Helical preference induced by various steric effects of nonpolar side chains was tested using higher level ab initio methods for well-known model systems such as: HCO-(beta-HVal-beta-HAla-beta-HLeu)2-NH2, HCO-(ACHC)6-NH2, HCO-(trans-ACPC)6-NH2, and HCO-(cis-ACPC)6-NH2. The relative stabilities determined by theoretical methods agreed well with most experimental data, supporting the theory that the local conformational preference influenced by steric effects is a key determining factor of the global fold both in solution and in the gas phase.

Parallel or polar strands of beta-peptides spontaneously form nanotubes of different sizes in a vacuum as determined by ab initio calculations. Stability and conformational features of [CH3CO-(beta-Ala)k-NHCH3]l (1 < or = k < or = 4, 2 < or = l < or = 4) models were computed at different levels of theory (e.g., B3LYP/6-311++G(d,p)// B3LYP/6-31G(d), with consideration of BSSE). For the first time, calculations demonstrate that sheets of beta-peptides display nanotubular characteristics rather than two-dimensional extended beta-layers, as is the case of alpha-peptides. Of the configurations studied, k = l = 4 gave the most stable nanotubular structure, but larger assemblies are expected to produce even more stable nanotubes. As with other nanosystems such as cyclodextrane, these nanotubes can also incorporate small molecules, creating a diverse range of applications for these flexible, biocompatible, and highly stable molecules. The various side chains of beta-peptides can make these nanosystems rather versatile. Energetic and structural features of these tubular model systems are detailed in this paper. It is hoped that the results presented in this paper will stimulate experimental research in the field of nanostructure technology involving beta-peptides.

The full conformational space was explored for an achiral and two chiral beta-peptide models: namely For-beta-Ala-NH2, For-beta-Abu-NH2, and For-beta-Aib-NH2. Stability and conformational properties of all three model systems were computed at different levels of theory: RHF/3-21G, B3LYP/6-311++G(d,p)//RHF/3-21G, B3LYP/6-311++G(d,p), MP2//B3LYP/6-311++G(d,p), CCSD//B3LYP/6-311++G(d,p), and CCSD(T)//B3LYP/6-311++G(d,p). In addition, ab initio E = E(phi, micro, psi) potential energy hypersurfaces of all three models were determined, and their topologies were analyzed to determine the inherent flexibility properties of these beta-peptide models. Fewer points were found and assigned than expected on the basis of Multidimensional Conformational Analysis (MDCA). Furthermore, it has been demonstrated, that the four-dimensional surface, E = E(phi, mu, psi), can be reduced into a three-dimensional one: E = E[phi, f(phi), psi]. This reduction of dimensionality of freedom of motion suggests that beta-peptides are less flexible than one would have thought. This agrees with experimental data published on the conformational properties of peptides composed of beta-amino acid residues.

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