Electrostatic pKa computations in proteins: Role of internal cavities

✍ Scribed by Tim Meyer; Gernot Kieseritzky; Ernst-Walter Knapp

• Book ID: 105358283
• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 801 KB
• Volume: 79
• Category: Article
• ISSN: 0887-3585
• DOI: 10.1002/prot.23092

✦ Synopsis

Abstract

The solvent accessible surface area (SASA) algorithm is conventionally used to characterize protein surfaces in electrostatic energy computations of proteins. Unfortunately, it often fails to find narrow cavities inside a protein. As a consequence p__K__~a~ computations based on this algorithm perform badly. In this study a new cavity‐algorithm is introduced, which solves this problem and provides improved p__K__~a~ values. The procedure is applied to 20 p__K__~a~ values of titratable groups introduced as point mutations in SNase variants, where crystal structures are available. The computations of these p__K__~a~s are particular challenging, since they are placed in a rather hydrophobic environment. For nine mutants, where the titratable residue is in contact with a large cavity, the RMSD between computed and measured p__K__~a~ values is 2.04, which is a considerable improvement as compared to the original results obtained with Karlsberg^+^ (http://agknapp.chemie.fu‐berlin.de/karlsberg/) that yielded an RMSD of 8.8. However, for 11 titratable residues the agreement with experiments remains poor (RMSD = 6.01). Considering 15 p__K__~a~s of SNase, which are in a more conventional less hydrophobic protein environment, the RMSD is 2.1 using the SASA‐algorithm and 1.7 using the new cavity‐algorithm. The agreement is reasonable but less good than what one would expect from the general performance of Karlsberg^+^ indicating that SNase belongs to the more difficult proteins with respect to p__K__~a~ computations. We discuss the possible reasons for the remaining discrepancies between computed and measured p__K__~a~s. Proteins 2011; © 2011 Wiley‐Liss, Inc.