PKa calculations

Although FEP is mostly useful for binding type of simulations rather than chemical reactions, it can be valuable for reduction potential and pKa calculations, which are of interest from many perspectives. For example, prediction of reliable pKa values of key groups can be used as a criterion for establishing a reliable microscopic model for complex systems. Technically, FEP calculation with QM/MM potentials is complicated by the fact that QM potentials are non-seperable [78], When the species subject to perturbation (A B) differ mainly in electronic structure but similar in nuclear connectivity (e.g., an oxidation-reduction pair), we find it is beneficial to use the same set of nuclear geometry for the two states [78], i.e., the coupling potential function has the form,... 

Table 7-1. Representative results from statistical analyses used to determine the values and statistical errors of 9 AGch(D)Oh/3 - for the pKa calculation of the zinc-bound water in CAIIa...

Figure 10-1. Thermodynamic cycle for the absolute pKa calculation of small molecules. Subscripts gas and aq denote gas- and aqueous-phase, respectively...

Figure 10-2. Thermodynamic cycle for the pKa calculation of proteins. Subscripts mod and prot refer to the model compound and protein, respectively...

Another advantage of PB based pKa calculations is that effects of electrolytes are readily accounted for in the PB equation. The Coulombic contribution in conjunction with salt dependence to the abnormally depressed pAVs of histidine in staphylococcal nuclease has been experimentally tested [56], Recently, the methodology used in the PB calculations (Eqs. 10-11 and 10-12) has been combined with the generalized Born (GB) implicit solvent model [94] to offer pKa predictions at a reduced computational cost [52],... 

The accuracy of PHMD methods and their feasibility for studying pH-dependent conformational phenomena of proteins can be assessed by pKa calculations. In this case, PHMD simulations are performed with several pH values. The resulting occupancy values for deprotonated states (.S dc prot) are plotted against pH (Figure 10-3). A titration curve and pATa values (Figure 10-3) can be obtained by fitting the data to the generalized HH equation (Eq. 10-5). 

The discrete protonation states methods have been tested in pKa calculations for several small molecules and peptides, including succinic acid [4, 25], acetic acid [93], a heptapeptide derived from ovomucoid third domain [27], and decalysine [61], However, these methods have sofar been tested on only one protein, the hen egg lysozyme [16, 61, 71], While the method using explicit solvent for both MD and MC sampling did not give quantitative agreement with experiment due to convergence difficulty [16], the results using a GB model [71] and the mixed PB/explicit... 

In an early work by Mertz and Pettitt, an open system was devised, in which an extended variable, representing the extent of protonation, was used to couple the system to a chemical potential reservoir [67], This method was demonstrated in the simulation of the acid-base reaction of acetic acid with water [67], Recently, PHMD methods based on continuous protonation states have been developed, in which a set of continuous titration coordinates, A, bound between 0 and 1, is propagated simultaneously with the conformational degrees of freedom in explicit or continuum solvent MD simulations. In the acidostat method developed by Borjesson and Hiinenberger for explicit solvent simulations [13], A. is relaxed towards the equilibrium value via a first-order coupling scheme in analogy to Berendsen s thermostat [10]. However, the theoretical basis for the equilibrium condition used in the derivation seems unclear [3], A test using the pKa calculation for several small amines did not yield HH titration behavior [13],... 

Lim C, Bashford D, Karplus M (1991) Absolute pKa calculations with continuum dielectric methods. JPhys Chem 95 5610-5620. 

Riccardi D, Schaefer P, Cui Q (2005) pKa Calculations in Solution and Proteins with QM/MM Free Energy Perturbation Simulations A Quantitative Test of QM/MM Protocols. J Phys Chem B 109 17715-17733. 

Simonson T, Carlsson J, Case DA (2004) Proton binding to proteins pKa calculations with explicit and implicit solvent models. J Am Chem Soc 126 4167-4180. 

In most pKa calculations with the standard method, a moderate to high (

molecular mechanics charge set is used. In cases where protonation induces a large protein conformational relaxation, this combination is likely to give a poor consistency between the two underlying free energy... 

Eberini, I. Baptista, A.M. Gianazza, E. Fraternali, F. Beringhelli, T., Reorganization in apo- and holo-ZJ-lactoglobulin upon pro to nation of Glu89 molecular dynamics and pKa calculations, Proteins 2004, 54, 744-758... 

When considering the topic of acid-base balance, there are two key terms with which you should be familiar. These are pH and pKa. Calculations of a patient s acid-base status will utilize these terms. 

Yoo, J., Cui, Q. Does arginine remain protonated in the lipid membrane Insights from microscopic pKa calculations. Biophys. J. 2008, 94, L61-3. 

Nielsen, J. E. and Vriend, G. (2001) Optimizing the hydrogen-bond network in Poisson-Boltzmann equation-based pKa calculations. Proteins 43,403-412. 

The principles behind the absolute pKa calculations in [46] are illustrated with the aid of Fig. 8.4. The program was Gaussian 98 [49], and several ab initio levels and solvation methods were explored the favored ones are given here, with values for acetic acid, CH3COOH ... 

ChemAxon, pKa Calculator Plugin, http //www.chemaxon.com/marvin/ chemaxon/marvin/help/calculator-plugins.html pka. 

More from pKaS Calculating the pN values for water acting as a base and as an acid... 

---