Improving the accuracy of protein pKa calculations: Conformational averaging versus the average structure

✍ Scribed by Herman W.T. van Vlijmen; Michael Schaefer; Martin Karplus

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 155 KB
• Volume: 33
• Category: Article
• ISSN: 0887-3585
• DOI: 10.1002/(sici)1097-0134(19981101)33:2<145::aid-prot1>3.0.co;2-i

✦ Synopsis

Several methods for including the conformational flexibility of proteins in the calculation of titration curves are compared. The methods use the linearized Poisson-Boltzmann equation to calculate the electrostatic free energies of solvation and are applied to bovine pancreatic trypsin inhibitor (BPTI) and hen egg-white lysozyme (HEWL). An ensemble of conformations is generated by a molecular dynamics simulation of the proteins with explicit solvent. The average titration curve of the ensemble is calculated in three different ways: an average structure is used for the pK a calculation; the electrostatic interaction free energies are averaged and used for the pK a calculation; and the titration curve for each structure is calculated and the curves are averaged. The three averaging methods give very similar results and improve the pK a values to approximately the same degree. This suggests, in contrast to implications from other work, that the observed improvement of pK a values in the present studies is due not to averaging over an ensemble of structures, but rather to the generation of a single properly averaged structure for the pK a calculation.