Abstract
Multiple variants of the AMBER all-atom force field were quantitatively evaluated with respect to their ability to accurately characterize helix-coil equilibria in explicit solvent simulations. Using a global distributed computing network, absolute conformational convergence was achieved for large ensembles of the capped A21 and Fs helical peptides. Further assessment of these AMBER variants was conducted via simulations of a flexible 164-residue five-helix-bundle protein, apolipophorin-III, on the 100 ns timescale. Of the contemporary potentials that had not been assessed previously, the AMBER-99SB force field showed significant helix-destabilizing tendencies, with beta bridge formation occurring in helical peptides, and unfolding of apolipophorin-III occurring on the tens of nanoseconds timescale. The AMBER-03 force field, while showing adequate helical propensities for both peptides and stabilizing apolipophorin-III, (i) predicts an unexpected decrease in helicity with ALA→ARG+ substitution, (ii) lacks experimentally observed 310 helical content, and (iii) deviates strongly from average apolipophorin-III NMR structural properties. As is observed for AMBER-99SB, AMBER-03 significantly overweighs the contribution of extended and polyproline backbone configurations to the conformational equilibrium. In contrast, the AMBER-99φ force field, which was previously shown to best reproduce experimental measurements of the helix-coil transition in model helical peptides, adequately stabilizes apolipophorin-III and yields both an average gyration radius and polar solvent exposed surface area that are in excellent agreement with the NMR ensemble.
Highlights
Simulating protein dynamics remains a daunting task in computational chemistry and biophysics
These modifications have aimed to improve upon the torsional potentials around the w and y dihedrals in protein backbones [2], which were fit to the relative quantum mechanical energies of alternate rotamers of small GLY and ALA peptides in Cornell’s seminal AMBER-94 force field [3]: (a) AMBER-96 recalibrates these parameters to accurately predict energy differences between constrained and extended ahelical conformations of ALA peptides [4]; (b) AMBER-99 refits the parameterization using calculations on representative ALA tetrapeptides [5]; and (c) the Garcia-Sanbonmatsu variant of AMBER94 zeroes both torsional potentials [6]
Following our initial publication of the AMBER-99w force field, we reported on the inability of this potential and other AMBER potentials to adequately characterize polyproline type II structure in the blocked ALA7 peptide [24], suggesting in that report that force field behavior should be dependent on peptide length, as highly diverging structural character has been observed in varying lengths of polyalanine peptides
Summary
Simulating protein dynamics remains a daunting task in computational chemistry and biophysics. In an effort to properly assess the conformational preferences and equilibria of model systems simulated under the various force fields in use by the computational community, we set out to systematically study contemporary potentials in their application to one of the most ubiquitous and fundamental of protein substructures: the a-helix [1,7,8,9]. These studies included the simulation of large ensembles of model helical peptides starting from fully helical and fully unfolded states to convergence of conformational equilibrium on the hundreds of nanoseconds timescale. AMBER-99w gave the best agreement with quantum mechanical sampling of the alanine dimer and a survey of alanine conformations in the Protein Data Bank (PDB) [7]
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