The interactions of phenylalanines in β-sheet-like structures from molecular orbital calculations using density functional theory (DFT), MP2, and CCSD(T) methods

Abstract

We present density functional theory calculations designed to evaluate the importance of π -stacking interactions to the stability of in-register Phe residues within parallel β-sheets, such as amyloids. We have used a model of a parallel H-bonded tetramer of acetylPheNH 2 as a model and both functionals that were specifically designed to incorporate dispersion effects (DFs), as well as, several traditional functionals which have not been so designed. None of the functionals finds a global minimum for the π -stacked conformation, although two of the DFs find this to be a local minimum. The stacked phenyls taken from the optimized geometries calculated for each functional have been evaluated using MP2 and CCSD(T) calculations for comparison. The results suggest that π -stacking does not make an important contribution to the stability of this system and (by implication) to amyloid formation.

Assessment of the Presence and Strength of H-Bonds by Means of Corrected NMR

“…However, there is also the distinct possibility that CH··O HBs are also present and add a substantial supplement to the interaction between the adjacent strands. This idea has been supported by a number of calculations over the years [62,63,64,83,84,85,86].…”

Self-Assembly of Phenylalanine-Based Molecules

“…Geometries that optimize the energetics of phenylalanine assemblies have also been studied by density-functional calculations. Three dominant structures were found for a system of four interacting phenylalanines 19 . One interacts only through the backbone with no indication of ⇡ stabilization.…”

Virtual and In Vitro Screens Reveal a Potential Pharmacophore that Avoids the Fibrillization of Aβ1–42

“…As shown in Fig 7A , the principal type of interactions that drive the selectivity of Aβ-α are electrostatic interactions with residues Glu22 and Asp23 and π–π interactions with Phe19 and Phe20. The formation of π–π interactions indicates the presence of an important moiety because the formation of strong π–π interactions between these chemical groups has been demonstrated to represent an intermediary stage in the unfolding process that drives the adoption of the β-sheet conformation [ 56 ].…”