Electrostatic Polarization Is Crucial for Reproducing pKa Shifts of Carboxylic Residues in Turkey Ovomucoid Third Domain

Abstract

We have computed pKa shifts for carboxylic residues of the serine protease inhibitor turkey ovomucoid third domain (residues Asp7, Glu10, Glu19, Asp27, and Glu43). Both polarizable and nonpolarizable empirical force fields were employed. Hydration was represented by the surface generalized Born and Poisson-Boltzmann continuum model. The calculations were carried out in the most physically straightforward fashion, by directly comparing energies of the protonated and deprotonated protein forms, without any additional parameter fitting or adjustment. Our studies have demonstrated that (i) the Poisson-Boltzmann solvation model is more than adequate in reproducing pKa shifts, most likely due to its intrinsically many-body formalism; (ii) explicit treatment of electrostatic polarization included in our polarizable force field (PFF) calculations appears to be crucial in reproducing the acidity constant shifts. The average error of the PFF results was found to be as low as 0.58 pKa units, with the best fixed-charges average deviation being 3.28 units. Therefore, the pKa shifts phenomena and the governing electrostatics are clearly many-body controlled in their intrinsic nature; (iii) our results confirm previously reported conclusions that pKa shifts for protein residues are controlled by the immediate environment of the residues in question, as opposed to long-range interactions in proteins. We are confident that our confirmation of the importance of explicit inclusion of polarization in empirical force fields for protein studies will be useful far beyond the immediate goal of accurate calculation of acidity constants.

Calculating pKa values for substituted phenols and hydration energies for other compounds with the first‐order fuzzy‐border continuum solvation model

“…These compounds were chosen as relevant in calculating pKa shifts of aspartic and glutamic acid residues of proteins (such as those calculated in Reference 1). Relevant results are presented in Table 8.…”

“…Thus, we were calculating the ΔG(aq, AH→A − ) and ΔG(gas, AH→A − ) terms in Equation 2. They were found as differences of the corresponding energies, just as we did in the previous studies described in References 1–3 and 16. Moreover, since the proton free energy of solvationΔG sol (H + ) has the same value for any molecular system, a carefully determined literature result 17 of −269.0 kcal/mol was used.…”

“…Our lab is just one of those utilizing the benefits of such models, and we have been able to do so in a number of projects, including those which involve calculating acidity constant values for both proteins and smaller molecular systems. 1–3 …”

ACKS2: Atom-condensed Kohn-Sham DFT approximated to second order

“…orthogonal to planar molecules, and is therefore widely used in PFFs. [44][45][46][47][48][49] These PFFs are often used in molecular dynamics (MD) simulations based on Born-Oppenheimer, 15 extended Lagrangian 20,36,50 (cfr. CarParrinello 51 ) or predictor-corrector 52 approaches to compute atomic charges and/or dipoles at each time step.…”

Electrostatic Fields Near the Active Site of Human Aldose Reductase: 1. New Inhibitors and Vibrational Stark Effect Measurements

“…Measurements of the strength and direction of these fields are therefore of great importance, and represent a long-standing biophysical challenge (9)(10)(11)(12)(13)(14)(15)(16). One strategy that has been developed in recent years is vibrational Stark effect (VSE 1 ) spectroscopy, which describes the influence of an electric field on a molecular vibrational frequency and can be observed through infrared spectroscopy (17,18).…”