Understanding the role of intramolecular ion-pair interactions in conformational stability using an ab initio thermodynamic cycle

TL;DR

This study introduces a thermodynamic cycle method based on ab initio calculations to accurately estimate intramolecular ion-pair interaction energies, aiding understanding of peptide conformational stability.

Contribution

It presents a novel thermodynamic cycle approach using density functional theory for evaluating intramolecular ion-pair energies in peptides and benchmark molecules.

Findings

Ion-pair energies agree within 2.5% for long linkers between methods.

The approach effectively models salt-bridge interactions in peptides.

Thermodynamic cycle simplifies calculations of intramolecular interactions.

Abstract

Intramolecular ion-pair interactions yield shape and functionality to many molecules. With proper orientation, these interactions overcome steric factors and are responsible for the compact structures of several peptides. In this study, we present a thermodynamic cycle based on isoelectronic and alchemical mutation to estimate intramolecular ion-pair interaction energy. We determine these energies for 26 benchmark molecules with common ion-pair combinations and compare them with results obtained using intramolecular symmetry-adapted perturbation theory. For systems with long linkers, the ion-pair energies evaluated using both approaches deviate by less than 2.5% in vacuum phase. The thermodynamic cycle based on density functional theory facilitates calculations of salt-bridge interactions in model tripeptides with continuum/microsolvation modeling, and four large peptides: 1EJG (crambin), 1BDK (bradykinin), 1L2Y (a mini-protein with a tryptophan cage), and 1SCO (a toxin from the scorpion venom).