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Anhydrous Monoalkylguanidines in Aprotic and Nonpolar Solvents: Models for Deprotonated Arginine Side Chains in Membrane Environments.

ABSTRACT: In this study, the synthesis of crystalline dodecylguanidine free base and its spectroscopic characterization in nonpolar environments are described. IR as well as 1H and 15N NMR spectra of the free base dissolved in aprotic solvents are substantially different from the previously reported spectra of arginine, or other monoalkylguanidinium compounds, at high hydroxide concentrations. The current results provide improved modeling for the spectroscopic signals that would be expected from a deprotonated arginine in a nonpolar environment. On the basis of our spectra of the authentic dodecylguanidine free base, addition of large amounts of aqueous hydroxide to arginine or other monoalklyguanidinium salts does not deprotonate them. Instead, hydroxide addition leads to the formation of a guanidinium hydroxide complex, with a dissociation constant near ?500 mM that accounts for the established arginine pK value of ?13.7. We also report a method for synthesizing a compound containing both phenol and free-base guanidine groups, linked by a dodecyl chain that should be generalizable to other hydrocarbon linkers. Such alkyl-guanidine and phenolyl-alkyl-guanidine compounds can serve as small-molecule models for the conserved arginine-tyrosine groupings that have been observed in crystallographic structures of both microbial rhodopsins and G-protein-coupled receptors.

SUBMITTER: Banyikwa AT

PROVIDER: S-EPMC6645140 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Anhydrous Monoalkylguanidines in Aprotic and Nonpolar Solvents: Models for Deprotonated Arginine Side Chains in Membrane Environments.

Banyikwa Andrew Toyi AT Miller Stephen E SE Krebs Richard A RA Xiao Yuewu Y Carney Jeffrey M JM Braiman Mark S MS

ACS omega 20171027 10

In this study, the synthesis of crystalline dodecylguanidine free base and its spectroscopic characterization in nonpolar environments are described. IR as well as <sup>1</sup>H and <sup>15</sup>N NMR spectra of the free base dissolved in aprotic solvents are substantially different from the previously reported spectra of arginine, or other monoalkylguanidinium compounds, at high hydroxide concentrations. The current results provide improved modeling for the spectroscopic signals that would be e ...[more]

PMID: 31457300

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Project description:The basic amino acids lysine (Lys) and arginine (Arg) play important roles in membrane protein activity, the sensing of membrane voltages, and the actions of antimicrobial, toxin, and cell-penetrating peptides. These roles are thought to stem from the strong interactions and disruptive influences of these amino acids on lipid membranes. In this study, we employ fully atomistic molecular dynamics simulations to observe, quantify, and compare the interactions of Lys and Arg with saturated phosphatidylcholine membranes of different thickness. We make use of both charged (methylammonium and methylguanidinium) and neutral (methylamine and methylguanidine) analogue molecules, as well as Lys and Arg side chains on transmembrane helix models. We find that the free energy barrier experienced by a charged Lys crossing the membrane is strikingly similar to that of a charged Arg (to within 2 kcal/mol), despite the two having different chemistries, H-bonding capability, and hydration free energies that differ by ?10 kcal/mol. In comparison, the barrier for neutral Arg is higher than that for neutral Lys by around 5 kcal/mol, being more selective than that for the charged species. This can be explained by the different transport mechanisms for charged or neutral amino acid side chains in the membrane, involving membrane deformations or simple dehydration, respectively. As a consequence, we demonstrate that Lys would be deprotonated in the membrane, whereas Arg would maintain its charge. Our simulations also reveal that Arg attracts more phosphate and water in the membrane, and can form extensive H-bonding with its five H-bond donors to stabilize Arg-phosphate clusters. This leads to enhanced interfacial binding and membrane perturbations, including the appearance of a trans-membrane pore in a thinner membrane. These results highlight the special role played by Arg as an amino acid to bind to, disrupt, and permeabilize lipid membranes, as well as to sense voltages for a range of peptide and protein activities in nature and in engineered bionanodevices.

Dataset Information

Anhydrous Monoalkylguanidines in Aprotic and Nonpolar Solvents: Models for Deprotonated Arginine Side Chains in Membrane Environments.

Publications

Anhydrous Monoalkylguanidines in Aprotic and Nonpolar Solvents: Models for Deprotonated Arginine Side Chains in Membrane Environments.

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