Integrating the intrinsic conformational preferences of noncoded α‐amino acids modified at the peptide bond into the noncoded amino acids database

Abstract

Recently, we reported a database (NCAD, Non-Coded Amino acids Database; http://recerca.upc.edu/imem/index.htm) that was built to compile information about the intrinsic conformational preferences of non-proteinogenic residues determined by quantum mechanical calculations, as well as bibliographic information about their synthesis, physical and spectroscopic characterization, the experimentally-established conformational propensities, and applications (J. Phys. Chem. B 2010, 114, 7413). The database initially contained the information available for α-tetrasubstituted α-amino acids. In this work, we extend NCAD to three families of compounds, which can be used to engineer peptides and proteins incorporating modifications at the –NHCO– peptide bond. Such families are: N-substituted α-amino acids, thio-α-amino acids, and diamines and diacids used to build retropeptides. The conformational preferences of these compounds have been analyzed and described based on the information captured in the database. In addition, we provide an example of the utility of the database and of the compounds it compiles in protein and peptide engineering. Specifically, the symmetry of a sequence engineered to stabilize the 310-helix with respect to the α-helix has been broken without perturbing significantly the secondary structure through targeted replacements using the information contained in the database.

Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity

“…Introduction of N-methyl groups causes significant consequences on peptide conformation, due in part to creation of a tertiary amide which loses a potential NH hydrogen-bond donor and may adopt energetically similar cis and trans isomers [47]. Computational analysis of the N'-methyl amides of N-acetyl-N-methyland N-acetyl-alanine indicated that repulsive interactions between the N-methyl and carbonyl oxygen moieties of the former abolished the low-energy minimum β-conformer adopted by the latter [48]. In cyclic peptides, N-methyl residues have also induced backbone f and ψ dihedral angles consistent with βand γ-turn conformers [49], as well as altered side chain χ geometry [50].…”

Systematic Exploration of Functional Group Relevance for Anti-Leishmanial Activity of Anisomycin

“…The L. infantum (MHOM/MA/67/ITMAP-263) wild-type strain (WT), as well as the resistant mutants Sb2000.1, AmB1000.1, and MF200.5 [ 29 , 30 , 31 , 32 , 33 ], which are respectively resistant to antimony (Sb III ), amphotericin B (AmB), and miltefosine (MF), were grown in M199 medium at 25 °C supplemented with 10% fetal bovine serum, 5 μg/mL of haemin at pH 7.0, 2000 μM Sb (Potassium antimonyl tartrate trihydrate, Sigma-Aldrich, Saint Louis, MO, USA), 200 μM of MF (Miltefosine, Cayman Chem, Ann Arbor, MI, USA) or 1 μM AmB (Amphotericin B solution, Sigma-Aldrich, Saint Louis, MO, USA). Leishmanicidal values were determined in Leishmania promastigotes by monitoring the replication of parasites after 72 h of incubation at 25 °C in the presence of increasing concentrations of the different compounds by measuring A 600 using a Cytation 5 machine (BioTek-Agilent, Santa Clara, CA 9, USA).…”

Sequence-based prediction of the solubility of peptides containing non-natural amino acids

“…One of the major issues in peptide drug development is the recognition by proteases and peptidases, which can be attenuated by changing the backbone through incorporation of amide bond mimics, D-isomers, β-amino acids, alteration of the termini or tetra-substituted amino acids 1,4,17,19,[31][32][33][34][35][36] . These mimics also tend to increase bioavailability, another issue which often plagues peptide drugs 17 as well as restrict conformation and therefore reduce flexibility 1,37,38 . Similar effects can also be caused by N-alkylations 1,17 , incorporation of aminoisobutyric acid 39 , other constraining amino acids 31,40,41 or by cyclisation 1,19,36,38 .…”