Location, average orientation and dynamics of amino acids in a membrane mimetic: a 2H-NMR and molecular dynamics study.

Abstract

A better understanding of how amino acids (AAs) associate with and partition into cell membranes is crucial for describing the passive AA-membrane interactions that underlie non-facilitated permeation. However, the average orientation, distribution, and dynamics of most AAs at the lipid bilayer and its interface remain poorly characterized. In this work, we investigated the behavior of four AAs (ALA, GLU, LEU and MET) dissolved in a discotic nematic bicellar lyotropic liquid-crystal membrane mimetic, based on sodium dodecyl sulfate (SDS) and 1-decanol (DeOH), using a combination of 2H-NMR spectroscopy and all-atom molecular dynamics (MD) simulations. The 2H-NMR spectra of selectively deuterated AAs confirmed that they are all associated with the bilayer, exhibiting significant quadrupole splittings. The more hydrophobic amino acids (LEU and MET) induce larger alkyl-chain disorder, while ALA leaves the bilayer order essentially unchanged. GLU produces an intermediate perturbation. MD provides a molecular-level picture of where and how each amino acid binds: all AAs anchor to the interface through their zwitterion, but their side chains adopt different preferential orientations governed by a hydrophobic/hydrophilic balance. ALA, which bears the smallest hydrophobic side chain, binds at the head-group layer without inserting its side chain. LEU and MET have more hydrophobic side chains and insert them into the hydrophobic region of the bilayer. GLU, the least associated of the four, binds only transiently through its zwitterion, with its anionic side chain oriented towards the water molecule and paired with Na+; therefore, its intermediate effect on the chain order suggests an electrostatic mechanism rather than insertion. The results show that passive AA-membrane association is governed by electrostatic anchoring of the zwitterion at the interface and by hydrophobic/hydrophilic partitioning of the side chain.

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