title: Exploring protein native states and large-scale conformational changes with a modified generalized born model.
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 approximately 1.5 A after 6 ns of simulation time. The structure of Barnase/Barstar complex is regenerated, starting from an unbound state, to within 1.9 A relative to the crystal structure of the complex.
authors.affiliation: Department of Computer Science, Virginia Tech, Blacksburg, Virginia, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Onufriev
authors.forename: Donald
authors.initials: D
authors.lastname: Bashford
authors.forename: David A
authors.initials: DA
authors.lastname: Case
mesh_terms: D001426:Bacterial Proteins; D003198:Computer Simulation; D008958:Models, Molecular; D016012:Poisson Distribution; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012260:Ribonucleases / Q000737:chemistry / Q000378:metabolism; D012984:Software; D012997:Solvents / Q000737:chemistry; D013205:Staphylococcal Protein A / Q000737:chemistry; D055672:Static Electricity; D013816:Thermodynamics; D013879:Thioredoxins / Q000737:chemistry; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D011506:Proteins; D012997:Solvents; D013205:Staphylococcal Protein A; D025801:Ubiquitin; C057438:barstar protein, Bacillus amyloliquefaciens; D013879:Thioredoxins; D012260:Ribonucleases; C019760:Bacillus amyloliquefaciens ribonuclease