Exploring protein native states and large-scale conformational changes with a modified generalized born model
Article first published online: 5 MAR 2004
Copyright © 2004 Wiley-Liss, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 55, Issue 2, pages 383–394, 1 May 2004
How to Cite
Onufriev, A., Bashford, D. and Case, D. A. (2004), Exploring protein native states and large-scale conformational changes with a modified generalized born model. Proteins, 55: 383–394. doi: 10.1002/prot.20033
- Issue published online: 18 MAR 2004
- Article first published online: 5 MAR 2004
- Manuscript Accepted: 5 OCT 2003
- Manuscript Received: 14 MAY 2003
- National Institutes of Health. Grant Number: M57513
- Generalized Born approximation;
- molecular dynamics;
Implicit solvation models provide, for many applications, a reasonably accurate and computationally effective way to describe the electrostatics of aqueous solvation. Here, a popular analytical Generalized Born (GB) solvation model is modified to improve its accuracy in calculating the solvent polarization part of free energy changes in large-scale conformational transitions, such as protein folding. In contrast to an earlier GB model (implemented in the AMBER-6 program), the improved version does not overstabilize the native structures relative to the finite-difference Poisson–Boltzmann continuum treatment. In addition to improving the energy balance between folded and unfolded conformers, the algorithm (available in the AMBER-7 and NAB molecular modeling packages) is shown to perform well in more than 50 ns of native-state molecular dynamics (MD) simulations of thioredoxin, protein-A, and ubiquitin, as well as in a simulation of Barnase/Barstar complex formation. For thioredoxin, various combinations of input parameters have been explored, such as the underlying gas-phase force fields and the atomic radii. The best performance is achieved with a previously proposed modification to the torsional potential in the Amber ff99 force field, which yields stable native trajectories for all of the tested proteins, with backbone root-mean-square deviations from the native structures being ∼1.5 Å after 6 ns of simulation time. The structure of Barnase/Barstar complex is regenerated, starting from an unbound state, to within 1.9 Å relative to the crystal structure of the complex. Proteins 2004;55:000–000. © 2004 Wiley-Liss, Inc.