HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article ACCEPTED PREPRINT Full Text (PDF) All Versions of this Article: ps.036335.108v1 17/11/1955    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Spassov, V. Z Articles by Yan, L. PubMed PubMed Citation Articles by Spassov, V. Z Articles by Yan, L. Social Bookmarking                   What's this?

A Fast and Accurate Computational Approach to Protein Ionization

Accelrys

(RECEIVED May 7, 2008; ACCEPTED August 15, 2008)

We report a very fast and accurate physics-based method to calculate pH dependent electrostatic effects in protein molecules and to predict the pK values of individual sites of titration. In addition, a CHARMm based algorithm is included to construct and refine the spatial coordinates of all hydrogen atoms at a given pH. The present method combines electrostatic energy calculations based on the Generalized Born approximation with an iterative mobile clustering approach to calculate the equilibria of proton binding to multiple titration sites in protein molecules. The use of the GBIM (Generalized Born with Implicit Membrane) CHARMm module makes it possible to model not only water-soluble proteins but membrane proteins as well. The method includes a novel algorithm for preliminary refinement of hydrogen coordinates, including the determination of the optimal proton binding centers in ambiguous cases such as the carboxyl groups of acidic residues. Another difference from existing approaches is that instead of monopeptides, a set of relaxed pentapeptide structures are used as model compounds based on a recent accurate experimental estimation of the pKa values of natural acidic and basic residues in Ala-Ala-X-Ala-Ala structures. Tests on a set of 24 proteins demonstrate the high accuracy of the method. On average, the rmsd between predicted and experimental pK values is close to 0.5 pK units on this data set, and the accuracy is achieved at a very low computational cost. The pH-dependent assignment of hydrogen atoms also shows very good agreement with protonation states and hydrogen-bond network observed in neutron-diffraction structures. The protonation states and hydrogen positions are predicted correctly for 94% of all 849 residues in a test set of five structures, including 100% of tautomeric states of histidines and 82% of Asn and Gln amide groups. There is only one adjustable parameter in the method: the value of intra-molecular dielectric constant. All other parameters are kept at their standard force field values. The method is implemented as a computational protocol in Accelrys Discovery Studio 2.0 and provides a fast and easy way to study the effect of pH on many important mechanisms such as enzyme catalysis, ligand binding, protein-protein interactions, and protein stability.

Keywords: Computational Analysis of Protein Structure; Protein structure prediction; Molecular mechanics/dynamics; Continuum Electrostatics; Protein Ionization; pK prediction

¹ E-mail: vss{at}accelrys.com

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?