title: Origin of intrinsic 3(10)-helix versus strand stability in homopolypeptides and its implications for the accuracy of the Amber force field.
abstract: Current all-atom force fields often fail to recognize the native structure of a protein as the lowest free energy minimum. One possible cause could be the mathematical form of the potential based on the assumption that the conformation of a residue is independent of its neighbors. Here, using quantum mechanical (QM) methods (MP2/6-31g**//HF/6-31g** and MP2/cc-pVDZ//cc-pVDZ//HF/cc-pVDZ), the intrinsic correctness of the gas phase terms (without solvation) of the Amber ff03 and ff99 potentials are examined by testing their ability to reproduce the relative 3(10)-helix versus extended structure stabilities in the gas phase for 1-7-residue alanine, valine, leucine, and isoleucine homopolypeptides. The 3(10)-helix versus extended state stability strongly depends on chain length and less on the amino acid identity. The helical conformation becomes lower in energy than the extended conformation for all tested peptides longer than two residues, and its stability increases with the increase of chain length. The ff03 potential better describes the 3(10)-helix versus extended state energy than ff99 and also reproduces the curvature of the relative helix-extended state energies. Therefore, the mathematical form of the Amber potential is sufficient to describe the local effect of 3(10)-helix versus extended structure stabilization in the gas phase. However, the energy curves are shifted and the backbone geometries differ compared with the QM results. This may cause significant geometric discrepancies between native and predicted structures. Therefore, extant molecular mechanics force fields, such as Amber, need refinement of their parameters to correctly describe helix-extended state energetics and geometry of major conformations.
authors.affiliation: Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, 250 14th Street, Atlanta, Georgia 30318, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Jagielska
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Skolnick
mesh_terms: D000465:Algorithms; D005740:Gases / Q000737:chemistry; D006860:Hydrogen Bonding; D010455:Peptides / Q000737:chemistry*; D044367:Phase Transition; D011487:Protein Conformation; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D005740:Gases; D010455:Peptides