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

Citations Over TimeTop 1% of 2004 papers

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.

Related Papers

• → The Folding Pathway of Barnase: The Rate-Limiting Transition State and a Hidden Intermediate under Native Conditions(2004)52 cited
• → Relationship between the Native-State Hydrogen Exchange and the Folding Pathways of Barnase(1999)19 cited
• → Direct folding simulation of α‐helices and β‐hairpins based on a single all‐atom force field with an implicit solvation model(2006)35 cited
• → Lack of definable nucleation sites in the rate-limiting transition state of barnase under native conditions 1 1Edited by C. R. Matthews(2002)18 cited
• → Elements of non-random structure in the unfolded states of proteins: location and possible implications for protein folding mechanisms(2003)