Protonation and Deprotonation Reaction of Aspartic Acid Side Chain Modulated by the Surrounding Dielectric Medium - AB Initio Quantum Chemical Studies on Aspartic Acid in Sixteen Different Solvents and Two Protein Structures

Abstract

Side chain of aspartic acid constitutes of carboxylate group, pKa equals to 3.7, in aqueous solution. However, large pKa shifts are often observed in protein structures. Several aspartic acid side chains are found in protonated form in protein NMR structures, for example, Asp26 in human thioredoxin, Asp96 in bacteriorhodopsin etc. Local micro-environment plays a crucial role in pKa shift of this amino acid side chain. Question asked in this study - how variation in the local dielectric medium influence protonation of aspartic acid side chain? To answer this question, we have performed Density Functional Theory (DFT) and Möller-Plesset second order perturbation theory (MP2) calculations on aspartic acid side chain in 16 different implicit solvents with varying dielectric constants. These calculations show that bond order of carboxylic-OH group decreases steeply in low dielectric range (ε between 1 to 9). Change in bond order within high dielectric range (ε > 20) is small. This calculation suggests that carboxylic-OH bond order in aspartic acid side chain should be high in protein hydrophobic region (low dielectric medium) compared to protein hydrophilic region (high dielectric medium). This fact was verified from bond order, electron densities on aspartic acids in two different proteins, ASP96 for bacteriorhodopsin and ASP52 for hen-egg-white-lysozyme, using hybrid quantum mechanics/molecular mechanics (QM/MM) approaches. The aspartic acids and the surrounding hydrophobic region was treated quantum chemically and the remaining part of the proteins were treated with classical mechanics. The details of the QM/MM analyses will be discussed.