Prediction of polyelectrolyte polypeptide structures using Monte Carlo conformational search methods with implicit solvation modeling

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Abstract
Many interesting proteins possess defined sequence stretches containing negatively charged amino acids. At present, experimental methods (X‐ray crystallography, NMR) have failed to provide structural data for many of these sequence domains. We have applied the dihedral probability grid‐Monte Carlo (DPG‐MC) conformational search algorithm to a series of N‐ and C‐capped polyelectrolyte peptides, (Glu)20, (Asp)20. (PSer)20, and (PSer‐Asp)10, that represent polyanionic regions in a number of important proteins, such as parathymosin, calsequestrin, the sodium channel protein, and the acidic biomineralization proteins. The atomic charges were estimated from charge equilibration and the valence and van der Waals parameters are from DREIDING. Solvation of the carboxylate and phosphate groups was treated using sodium counterions for each charged side chain (one Na+ for COO−; two Na for CO(PO3)−2) plus a distance‐dependent (shielded) dielectric constant, ϵ = ϵ0R, to simulate solvent water. The structures of these polyelectrolyte polypeptides were obtained by the DPG‐MC conformational search with ϵ0 = 10, followed by calculation of solvation energies for the lowest energy conformers using the protein dipole‐Langevin dipole method of Warshel. These calculations predict a correlation between amino acid sequence and global folded conformational minima: 1 Poly‐L‐Glu20, our structural benchmark, exhibited a preference for right‐handed α‐helix (47% helicity), which approximates experimental observations of 55–60% helicity in solution. 2 For Asp‐ and PSer‐containing sequences, all conformers exhibited a low preference for right‐handed α‐helix formation (≤10%), but a significant percentage (?20% or greater) of β‐strand and β‐turn dihedrals were found in all three sequence cases: (1) Aspn forms supercoil conformers, with a 2:1:1 ratio of β‐turn:β‐strand:α‐helix dihedral angles; (2) PSer20 features a nearly 1:1 ratio of β‐turn:β‐sheet dihedral preferences, with very little preference for α‐helical structure, and possesses short regions of strand and turn combinations that give rise to a collapsed bend or hairpin structure; (3) (PSer‐Asp)10 features a 3:2:1 ratio of β‐sheet:β‐turn:α‐helix and gives rise to a superturn or C‐shaped structure.