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pKa Units (pka + unit)
Selected AbstractsPrediction of pKa shifts in proteins using a combination of molecular mechanical and continuum solvent calculationsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 15 2004Bernd Kuhn Abstract The prediction of pKa shifts of ionizable groups in proteins is of great relevance for a number of important biological phenomena. We present an implementation of the MM-GBSA approach, which combines molecular mechanical (MM) and generalized Born (GB) continuum solvent energy terms, to the calculation of pKa values of a panel of nine proteins, including 69 individual comparisons with experiment. While applied so far mainly to the calculation of biomolecular binding free energies, we show that this method can also be used for the estimation of protein pKa shifts, with an accuracy around 1 pKa unit, even for strongly shifted residues. Our analysis reveals that the nonelectrostatic terms that are part of the MM-GBSA free energy expression are important contributors to improved prediction accuracy. This suggests that most of the previous approaches that focus only on electrostatic interactions could be improved by adding other nonpolar energy terms to their free energy expression. Interestingly, our method yields best accuracy at protein dielectric constants of ,int = 2,4, which is in contrast to previous approaches that peak at higher ,int , 8. An important component of our procedure is an intermediate minimization step of each protonation state involving different rotamers and tautomers as a way to explicitly model protein relaxation upon (de)protonation. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1865,1872, 2004 [source] Basicity of Guanidines with Heteroalkyl Side Chains in AcetonitrileEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 30 2008Mirjana Eckert-Maksi Abstract The pKa values of seven novel guanidine derivatives, six of them possessing heteroalkyl substituents capable of forming intramolecular hydrogen bonds, were determined in acetonitrile (MeCN) by using the UV/Vis spectrophotometric titration method. The obtained pKa values range from 24.7 to 27.2. The most basic among the studied guanidines was found to be by ca. 4 pKa units more basic than thewell-known superbase N1,N1,N3,N3 -tetramethylguanidine (TMG). The trends in the changes in the measured pKa values were compared with the experimental (determined by the extended kinetic method) and theoretical [B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d)] gas-phase proton affinities. It was shown that basicity ordering of the bases with dimethylaminopropyl substituents in acetonitrile follows the trend encountered in the gas phase. However, this is not the case for the methoxypropyl-substituted guanidines indicating that in these molecules formation of the intramolecular hydrogen bonds is to large extent hindered due to solvation by acetonitrile.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source] Accurate prediction of basicity in aqueous solution with COSMO-RSJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2006Frank Eckert Abstract The COSMO-RS method, a combination of the quantum chemical dielectric continuum solvation model COSMO with a statistical thermodynamics treatment for realistic solvation simulations, has been used for the prediction of base pKa constants. For a variety of 43 organic bases the directly calculated values of the free energies of dissociation in water showed a very good correlation with experimental base pKa values (r2 = 0.98), corresponding to a standard deviation of 0.56 pKa units. Thus, we have an a priori prediction method for base pKa with the regression constant and the slope as only adjusted parameters. In accord with recent findings for pKa acidity predictions, the slope of pKa vs. ,Gdiss was significantly smaller than the theoretically expected value of 1/RTln(10). The predictivity of the presented method is general and not restricted to certain compound classes, but systematic corrections of 1 and 2 pKa units for secondary and tertiary aliphatic amines are required, respectively. The pKa prediction method was validated on a set of 58 complex multifunctional drug-like compounds, yielding an RMS accuracy of 0.66 pKa units. © 2005 Wiley Periodicals, Inc. J Comput Chem 27: 11,19, 2006 [source] Analysis of Linear Free-Energy Relationships Combined with Activation Parameters Assigns a Concerted Mechanism to Alkaline Hydrolysis of X-Substituted Phenyl DiphenylphosphinatesCHEMISTRY - A EUROPEAN JOURNAL, Issue 24 2008Ik-Hwan Um Prof. Abstract A kinetic study is reported for alkaline hydrolysis of X-substituted phenyl diphenylphosphinates (1,a,i). The Brønsted-type plot for the reactions of 1,a,i is linear over 4.5 pKa units with ,lg=,0.49, a typical ,lg value for reactions which proceed through a concerted mechanism. The Hammett plots correlated with ,o and ,, constants are linear but exhibit many scattered points, while the corresponding Yukawa,Tsuno plot results in excellent linear correlation with ,=1.42 and r=0.35. The r value of 0.35 implies that leaving-group departure is partially advanced at the rate-determining step (RDS). A stepwise mechanism, in which departure of the leaving group from an addition intermediate occurs in the RDS, is excluded since the incoming HO, ion is much more basic and a poorer nucleofuge than the leaving aryloxide. A dissociative (DN + AN) mechanism is also ruled out on the basis of the small ,lg value. As the substituent X in the leaving group changes from H to 4-NO2 and 3,4-(NO2)2, ,H,, decreases from 11.3,kcal,mol,1 to 9.7 and 8.7,kcal,mol,1, respectively, while ,S,, varies from ,22.6,cal,mol,1,K,1 to ,21.4 and ,20.2,cal,mol,1,K,1, respectively. Analysis of LFERs combined with the activation parameters assigns a concerted mechanism to the current alkaline hydrolysis of 1,a,i. [source] Osmium(II) and Ruthenium(II) Arene Maltolato Complexes: Rapid Hydrolysis and Nucleobase BindingCHEMISTRY - A EUROPEAN JOURNAL, Issue 9 2007Abstract Density functional calculations show that aquation of [Os(,6 -arene)(XY)Cl]n+ complexes is more facile for complexes in which XY=an anionic O,O-chelated ligand compared to a neutral N,N-chelated ligand, and the mechanism more dissociative in character. The O,O-chelated XY=maltolato (mal) [M(,6 - p -cym)(mal)Cl] complexes, in which p -cym=p -cymene, M=OsII (1) and RuII (2), were synthesised and the X-ray crystal structures of 1 and 2,2,H2O determined. Their hydrolysis rates were rapid (too fast to follow by NMR spectroscopy). The aqua adduct of the OsII complex 1 was 1.6,pKa units more acidic than that of the RuII complex 2. Dynamic NMR studies suggested that O,O-chelate ring opening occurs on a millisecond timescale in coordinating proton-donor solvents, and loss of chelated mal in aqueous solution led to the formation of the hydroxo-bridged dimers [(,6 - p -cym)M(,-OH)3M(,6 - p -cym)]+. The proportion of this dimer in solutions of the OsII complex 1 increased with dilution and it predominated at micromolar concentrations, even in the presence of 0.1,M NaCl (conditions close to those used for cytotoxicity testing). Although 9-ethylguanine (9-EtG) binds rapidly to OsII in 1 and more strongly (log,K=4.4) than to RuII in 2 (log,K=3.9), the OsII adduct [Os(,6 - p -cym)(mal)(9EtG)]+ was unstable with respect to formation of the hydroxo-bridged dimer at micromolar concentrations. Such insights into the aqueous solution chemistry of metal,arene complexes under biologically relevant conditions will aid the rational design of organometallic anticancer agents. [source] | ||||||||||