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

Abstract

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

Simulating and analysing configurational landscapes of protein–protein contact formation

“…in this space, the sampling of configurations can neither be easily visualized nor can its essential features be grasped without further analysis. This problem can be addressed by dimensionality reduction to obtain a low-dimensional representation [16,17].…”

Trans–Cis Proline Switches in a Pentameric Ligand-Gated Ion Channel: How They Are Affected by and How They Affect the Biomolecular Environment

“…In this work, we explore the trans-cis isomerization of Pro281 in the 5-HT 3 receptor with the specific goal to assess how such process is affected by and, in turn, affects the structural and electrostatic environment of the ion channel, using molecular dynamics and the enhanced sampling method metadynamics, [28][29][30] which has been successfully used to accelerate rare events and explore free energies in small and large biomolecules [31][32][33] and prolinecontaining systems. 21,[34][35][36][37][38] Our receptor model is based on the 5-HT 3 R X-ray structure by Hassaine et al 8 and includes the full ECD and TMD, embedded in a lipid bilayer in a solvated environment.…”

“…In this work, we explore the trans – cis isomerization of Pro281 in the 5-HT 3 receptor with the specific goal to assess how such a process is affected by and, in turn, affects the structural and electrostatic environment of the ion channel, using molecular dynamics and the enhanced sampling method metadynamics, − which has been successfully used to accelerate rare events and explore free energies in small and large biomolecules − and proline-containing systems. ,− Our receptor model is based on the 5-HT 3 R X-ray structure by Hassaine et al and includes the full ECD and TMD, embedded in a lipid bilayer in a solvated environment. We carried out metadynamics calculations to estimate the free energy landscape of the isomerization, as well as a series of molecular dynamics simulations to assess the cumulative/cooperative action of multiple proline switches on the channel and, in particular, on the selectivity filter.…”

Proline isomerization effects in the amyloidogenic protein β2-microglobulin

“…Such protocol has been previously tested for β 2 -m in different situations [48][49][50][51] . OPLS-AA is known to produce larger torsional barriers than CHARMM and AMBER 8,40,52,53 . Despite the overestimation, the OPLS-AA force field is expected to qualitatively compare the free proline dipeptide isomerization with the same process in complex environments like proteins.…”