α-Aminoisobutyric acid

The N-terminus of the B-chain of insulin may adopt two alternative conformations designated as the T- and R-states. Despite the recent structural insight into insulin-insulin receptor (IR) complexes, the physiological relevance of the T/R transition is still unclear. Hence, this study focused on the rational design, synthesis, and characterization of human insulin analogues structurally locked in expected R- or T-states. Sites B3, B5, and B8, capable of affecting the conformation of the N-terminus of the B-chain, were subjects of rational substitutions with amino acids with specific allowed and disallowed dihedral φ and ψ main-chain angles. α-Aminoisobutyric acid was systematically incorporated into positions B3, B5, and B8 for stabilization of the R-state, and N-methylalanine and d-proline amino acids were introduced at position B8 for stabilization of the T-state. IR affinities of the analogues were compared and correlated with their T/R transition ability and analyzed against their crystal and nuclear magnetic resonance structures.

Some modified octapeptide analogs of somatostatin with the following structure D-Phe-c(Cys-Phe-D-Trp-Xxx-Yyy-Cys)-Thr-NH2, where Xxx is Lys or Orn and Yyy is Aib (α-aminoisobutyric acid), Ac5c (1-aminocyclopentanecarboxylic acid) or Ac6c (1-aminocyclohexane carboxylic acid) have been synthesized. The peptides were prepared by standard Fmoc-solid phase peptide chemistry method. The direct disulphide bond formation has been employed on the solid phase by Tl(CF3CO2)3. The cytotoxic effects of the compounds were tested in vitro against a panel of tumor cell lines: HT-29 (human colorectal cancer cell line), MDA-MB-23 (human breast cancer cell line), Hep-G2 (human hepatocellular carcinoma cell line), HeLa (cervical cancer cell line) and normal human diploid cell line Lep-3. The new peptides exhibited different concentration-dependent antiproliferative effect against the tumor cell lines after 24 h treatment. The compounds were most effective to the HT-29 tumor cells.

Based on a given time series, data-driven Langevin modeling aims to construct a low-dimensional dynamical model of the underlying system. When dealing with physical data as provided by, e.g., all-atom molecular dynamics simulations, effects due to small damping may be important to correctly describe the statistics (e.g., the energy landscape) and the dynamics (e.g., transition times). To include these effects in a dynamical model, an algorithm that propagates a second-order Langevin scheme is derived, which facilitates the treatment of multidimensional data. Adopting extensive molecular dynamics simulations of a peptide helix, a five-dimensional model is constructed that successfully forecasts the complex structural dynamics of the system. Neglect of small damping effects, on the other hand, is shown to lead to significant errors and inconsistencies.

Three types of stabilized helical peptides containing disulfide bonds, C-C cross-linked side chains, or α,α-disubstituted amino acids (2-aminoisobutyric acid (Aib)) were designed and synthesized as inhibitors of estrogen receptor (ER)-coactivator interactions. Furthermore, heptaarginine (R7)-conjugated versions of the peptides were prepared, and their effects on ER-mediated transcription were evaluated at the cellular level (in ER-positive T47D cells). Among them, the R7-conjugated peptides 11 and 12 downregulated the mRNA expression of pS2 (an ER-mediated gene whose expression is upregulated by 17β-estradiol) by 95% (at a dose of 10 μM) and 87% (at a dose of 3 μM), respectively.