Exploring protein native states and large‐scale conformational changes with a modified generalized born model

TLDR

Implicit solvation models offer a reasonably accurate and computationally efficient way to describe aqueous electrostatics. The study modifies a Generalized Born solvation model to better compute solvent polarization during large‑scale protein conformational changes. The modified GB model is implemented in AMBER‑7 and NAB, with parameter tuning (force fields, atomic radii) performed on thioredoxin. The improved GB model yields accurate energy balances and stable native trajectories (RMSD ~1.5 Å) in long MD simulations of several proteins and successfully recovers the Barnase/Barstar complex within 1.9 Å of the crystal structure. © 2004 Wiley‑Liss, Inc.; Proteins 2004;55:000–000.

Abstract

Abstract 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.