Conformational Properties of Triazole Foldamers

SNIC 2018/3-275


SNAC Medium Compute

Principal Investigator:

Nina Kann


Chalmers tekniska högskola

Start Date:


End Date:


Primary Classification:

10407: Theoretical Chemistry




In the last two decades peptidic foldamers have emerged as novel artificial oligomers with properties and structural diversity similar to that of natural peptides. Possessing several interesting and important features which their natural representatives lack, they have a great potential for applications in various fields from nanotechnology to pharmaceutics. Among these, foldamers containing 1,4- and 1,5-substitued triazole amino acids are easily prepared and offer increased side chain variation, but their structural capabilities have not yet been widely explored [1]. Ealier we have performed a systematic study exploring the conformational space for the two most important basic units of this set of compounds, the 1,2,4- (4Tzl) and the 1,2,5- (5Tzl) triazole amino acids using quantum chemical exhaustive conformation analysis and solution phase NMR spectroscopy in different solvents [2]. Owing to the computational methods, all possible conformations of these compounds were scanned and their potential minima were located using several theoretical approaches (e.g. B3LYP/6-311++G(2d,2p), wB97X-D/6-311++G(2d,2p) and MP2/6-311++G(2d,2p) ). Results demonstrate that the 5Tzl derivatives have 11 low energy conformers leading to a great structural diversity with relative energies lying close to each other. In contrast, 4Tzl have much lower amount of energetically stable conformers, which in principle offer only extended conformations. In a previous application we performed the following: 1. Characterized the conformational properties of all possible chiral building units for both 1,4 and 1,5 triazole amino acids, 2. Built oligomer peptides with folded secondary structures and characterize their properties in view of increasingly complex side chain patterns. We used QM calculations employing B3LYP, wB97XD functionals and middle sized basis sets, to optimize cpu resources, i.e. 6-31+G(d,p) [3]. The results were in part used for a review appearing in Chemical Reviews, a leading high impact journal in chemistry (IF: 37.6) [4]. 3. In the last year we have performed several MD simulations on these compounds, allowing investigation of triazoles and other non-nautral insertions in 1. natural peptides as inserted into these; 2. as foldamers, where triazole and other non-natural oligomers are presented. The continuation of this project aims to address now the conformational properties of these compounds in water, or in a lipid bilayer environments. After the initial tests, it became obvious that we need to perform two types of calculations: A: Triazole parametrization, using QM calculations and Gaussian B: Investigation of oligomers by MD simulations in water as well as in a lipid bilayer using Gromacs and NAMD. [1] Johansson, Hermansson, Kann, Nordén, Beke-Somfai: d-Peptides from RuAAC-Derived 1,5-Disubstituted Triazole Units, EJOC 2014, 13, 2703 [2] Kann, Johansson, Beke-Somfai: Conformational properties of 1,4- and 1,5-substituted 1,2,3-triazole amino acids – building units for peptidic foldamers, OBC, 2015, 13, 2776 [3] Manuscript submitted [4] J. Johansson, T. Beke-Somfai, A. Said Stalsmeden, N. Kann: Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism and Applications, Chemical Reviews, 2016, 116, 14726-14768