Mapping the conformational free energy of aspartic acid in the gas phase and in aqueous solution

Federico Comitani,Michele Ceriotti,Carla Molteni,Kevin Rossi,M Eugenia Sanz

doi:10.1063/1.4979519

Abstract

The conformational free energy landscape of aspartic acid, a proteogenic amino acid involved in a wide variety of biological functions, was investigated as an example of the complexity that multiple rotatable bonds produce even in relatively simple molecules. To efficiently explore such a landscape, this molecule was studied in the neutral and zwitterionic forms, in the gas phase and in water solution, by means of molecular dynamics and the enhanced sampling method metadynamics with classical force-fields. Multi-dimensional free energy landscapes were reduced to bi-dimensional maps through the non-linear dimensionality reduction algorithm sketch-map to identify the energetically stable conformers and their interconnection paths. Quantum chemical calculations were then performed on the minimum free energy structures. Our procedure returned the low energy conformations observed experimentally in the gas phase with rotational spectroscopy [M. E. Sanz et al., Phys. Chem. Chem. Phys. 12, 3573 (2010)]. Moreover, it provided information on higher energy conformers not accessible to experiments and on the conformers in water. The comparison between different force-fields and quantum chemical data highlighted the importance of the underlying potential energy surface to accurately capture energy rankings. The combination of force-field based metadynamics, sketch-map analysis, and quantum chemical calculations was able to produce an exhaustive conformational exploration in a range of significant free energies that complements the experimental data. Similar protocols can be applied to larger peptides with complex conformational landscapes and would greatly benefit from the next generation of accurate force-fields.

Highlights

Aspartic acid (Asp) is a non-essential α-amino acid involved in a number of metabolic functions, from the synthesis of proteins and biomolecules to the gluconeogenesis and the activation of N-methyl-D-aspartate (NMDA) receptors, important for synaptic plasticity and memory functions
Rotational spectroscopy experiments are able to extract information for the most populated low energy conformers in the gas phase and they are usually aided by computational methods to map the potential energy surface and predict conformational abundances
We have shown how a powerful protocol, which combines classical molecular dynamics (MD) simulations enhanced by metadynamics and the dimensionality reduction algorithm sketchmap, allowed us to efficiently explore the conformational free energy landscape, at finite temperature and at a relatively low computational cost, of a typical amino acid, Asp, in the neutral and zwitterionic forms, in the gas phase and in aqueous solution

Summary

Introduction

Aspartic acid (Asp) is a non-essential α-amino acid involved in a number of metabolic functions, from the synthesis of proteins and biomolecules to the gluconeogenesis and the activation of N-methyl-D-aspartate (NMDA) receptors, important for synaptic plasticity and memory functions. Asp side chain is a carboxyl group, usually deprotonated and negatively charged under physiological conditions, which is present in numerous protein active sites.. Asp side chain is a carboxyl group, usually deprotonated and negatively charged under physiological conditions, which is present in numerous protein active sites.1 This amino acid is found in the neutral form in the gas phase and in the zwitterionic form in aqueous solution and in crystals. In the latter form, the hydrogen of the Cα–COOH group is donated to the nitrogen to form an NH3+ amino group, as shown, resulting into opposite charges for these two moieties.. The most powerful technique for conformational identification in the gas phase is rotational spectroscopy, which has been successfully applied in combination with laser ablation to determine the conformations of many natural amino acids. In the condensed phases, methods such as NMR and X-ray crystallography are widely used. Theoretically, stable/metastable conformers can be identified, for example, by scanning the torsional angles at small intervals, 0021-9606/2017/146(14)/145102/11

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