Conformation and Self-Assembly of the Transmembrane Peptide Gramicidin A: Insights from ion Mobility Spectrometry and Molecular Dynamics

Abstract

Gramicidin A which is composed of alternating L- and D-amino acids is a naturally occurring pentadecapeptide from Bacillus brevis known to form monovalent metal ion channels in lipid membranes. The active form is a noncovalently bound dimer. The conformation and self-assembly behavior of gramicidin A highly depends on the solution environment. In this presentation, we report the use of electrospray-ion mobility-mass spectrometry to study the conformation of alkali metals adducts of gramicidin A monomer, as well as the monomerization and conformer interconversion equilibrium of gramicidin A dimer as a function of the solvent. The conformation of gramicidin A monomer vary significantly upon binding different metal adducts. Enhanced sampling molecular dynamics simulations are performed on alkali metals adducts to provide thermodynamics information of different conformers and gain insights of the interaction of different metal ions with the monomer. The kinetics of the monomerization and conformer interconversion processes of dimer in various alcohol solutions (Ethanol, 1-Propanol and, Isobutanol) are monitored by using the ion mobility profile of the monomer and the dimer. The rate constants and the temperature dependence of the rate constants of the monomer compare well with literature values which were obtained by using fluorescence. Furthermore, we found that the water content in the alcohol solution greatly influences the self-assembly process significantly. The role of water in catalyzing the conformer interconversion is being investigated further. Ion mobility spectrometry (IMS) combined with molecular dynamics simulations is a merging technique for conformational analysis of gas-phase low-lying energy level structures of biomolecules. In this study, we will demonstrate that this gas phase technique can also be of utility in studying a solution phase structural dynamics problem.