Abstract
Hydrogen constitutes nearly half of all atoms in proteins and their positions are essential for analyzing hydrogen-bonding interactions and refining atomic-level structures. However, most protein structures determined by experiments or computer prediction lack hydrogen coordinates. We present a new algorithm, HAAD, to predict the positions of hydrogen atoms based on the positions of heavy atoms. The algorithm is built on the basic rules of orbital hybridization followed by the optimization of steric repulsion and electrostatic interactions. We tested the algorithm using three independent data sets: ultra-high-resolution X-ray structures, structures determined by neutron diffraction, and NOE proton-proton distances. Compared with the widely used programs CHARMM and REDUCE, HAAD has a significantly higher accuracy, with the average RMSD of the predicted hydrogen atoms to the X-ray and neutron diffraction structures decreased by 26% and 11%, respectively. Furthermore, hydrogen atoms placed by HAAD have more matches with the NOE restraints and fewer clashes with heavy atoms. The average CPU cost by HAAD is 18 and 8 times lower than that of CHARMM and REDUCE, respectively. The significant advantage of HAAD in both the accuracy and the speed of the hydrogen additions should make HAAD a useful tool for the detailed study of protein structure and function. Both an executable and the source code of HAAD are freely available at http://zhang.bioinformatics.ku.edu/HAAD.
Highlights
Hydrogen constitutes nearly half of all atoms in protein molecules and plays an important role in controlling the folding kinetics and in stabilizing the native state through hydrophobic interactions and hydrogen bonding [1,2,3,4]
Based on a test using seven protein structures solved by X-ray crystallography and neutron diffraction, the authors concluded that REDUCE, WHAT IF and MCCE are among the best methods for placing hydrogen atoms
It shows that the Hatoms added by HAAD have a lower RMSD to the experimental structures than those added by HBUILD and REDUCE in all the hydrogen atoms (H-atoms) categories except spH1
Summary
Hydrogen constitutes nearly half of all atoms in protein molecules and plays an important role in controlling the folding kinetics and in stabilizing the native state through hydrophobic interactions and hydrogen bonding [1,2,3,4]. Most protein structures solved by X-ray crystallography in the Protein Data Bank (PDB) and structural models generated by computer programs (e.g. SCWRL [16] and MODELLER [17]) lack hydrogen atoms, which necessitates the development of programs that can predict hydrogen positions accurately and quickly. MCCE [18] places the non-hydroxyl hydrogen atoms using standard geometric values for the bond lengths and bond angles, while the hydroxyl hydrogen atom positions are optimized by Monte Carlo simulations guided by an energy function consisting of torsion, excluded volume, solvation, and electrostatic terms. Based on a test using seven protein structures solved by X-ray crystallography and neutron diffraction, the authors concluded that REDUCE, WHAT IF and MCCE are among the best methods for placing hydrogen atoms. For atomic protein structure simulations[25] and atomic force field based protein structure refinement [26], where detailed hydrogen-
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