Toward a rational design of β‐peptide structures

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Abstract
Intrinsic conformational characteristics of β‐peptides built up from simple achiral and chiral β‐amino acid residues (i.e., HCO‐β‐Ala‐NH2, HCO‐β‐Abu‐NH2) were studied using quantum chemical calculations and1H‐NMR spectroscopy. A conformer‐based systematic and uniform nomenclature was introduced to differentiate conformers. Geometry optimizations were performed on all homoconformers of both HCO‐(β‐Ala)k‐NH2and HCO‐(β‐Abu)k‐NH2(1 ≤k≤ 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 initiopopulation distribution of hexapeptides and the conformational ensemble of synthetic models composed of β‐Ala and β‐Abu studied using1H‐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 levelab initiomethods for well‐known model systems such as: HCO‐(β‐HVal‐β‐HAla‐β‐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. © 2005 Wiley Periodicals, Inc. J Comput Chem 27: 20–38, 2006

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