# Investigation of the Effect of C-Terminal Adjacent Phenylalanine Residues on Asparagine Deamidation by Quantum Chemical Calculations

## TL;DR

This study uses quantum calculations to explore how a phenylalanine residue affects the deamidation rate of asparagine in a lens protein.

## Contribution

The study reveals how the orientation of phenylalanine's side chain influences asparagine deamidation through computational analysis.

## Key findings

- The orientation of the Phe side chain affects the activation barrier for Asn deamidation.
- Interaction between Phe's aromatic ring and Asn's amide group lowers the activation barrier.
- These findings align with experimentally observed structures of γS-crystallin.

## Abstract

The deamidation rate is relatively high for Asn residues with Phe as the C-terminal adjacent residue in γS-crystallin, which is one of the human crystalline lens proteins. However, peptide-based experiments indicated that bulky amino acid residues on the C-terminal side impaired Asn deamination. In this study, we hypothesized that the side chain of Phe affects the Asn deamidation rate and investigated the succinimide formation process using quantum chemical calculations. The B3LYP density functional theory was used to obtain optimized geometries of energy minima and transition states, and MP2 and M06-2X calculations were used to obtain the single-point energy. Activation barriers and rate-determining step changed depending on the orientation of the Phe side chain. In pathways where an interaction occurred between the benzene ring and the amide group of the Asn residue, the activation barrier was lower than in pathways where this interaction did not occur. Since the aromatic ring is oriented toward the Asn side in experimentally determined structures of γS-crystallin, the above interaction is considered to enhance the Asn deamidation.