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Does Arginine Remain Protonated in the Lipid Membrane? Insights from Microscopic pK_a Calculations

Jejoong Yoo ^* and Qiang Cui ^* 

^* Graduate Program of Biophysics, and Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706

Correspondence: Address reprint requests and inquiries to Qiang Cui, E-mail: cui{at}chem.wisc.edu.

Free energy perturbation calculations are carried out to estimate the effective pK_a of an arginine (Arg) sidechain as a function of its location in the dipalmitoylphosphatidylcholine bilayer. Similar to previous all-atom simulations of the voltage sensor domain of a potassium channel in the membrane with charged Arg residues, the membrane and water structures deform to stabilize the charge of the Arg analog. As a result, the computed pK_a is >7 throughout the membrane although the value is very close to 7 near the center of the bilayer. With additional stabilizations from negatively charged amino acids or lipid molecules, it is reasonable to expect that Arg in membrane proteins (once in the membrane) can adopt the protonated state despite the low dielectric nature of the bulk lipid membrane.