Validation of nitroxyl spin-label force-field parameters through moleculardynamics simulations

A molecular mechanics parameter set for the nitroxyl spin-label 3-formyl-2, 2,5,5-tetramethyl-1-oxypyrroline was developed by application of Gaussian94 at the HF/6-31G(d) level suitable for use in molecular dynamics simulation s. The parameter set was validated through molecular dynamics calculations for the methyl eater of N-(2,2,5,5-tetramethyl-l-oxypyrrolinyl-3-carboxyl)- L-tryptophan to simulate its conformation and structure in methanol and in chloroform at 300 K with use of the program package CHARMM. Excellent agree ment of structural parameters derived by molecular dynamics simulations of the solute in both solvent systems was observed with the structure and conf ormation of the solute defined through electron nuclear double resonance st udies [Wells, G.B. et al., J Am Chem Soc 1990, 112, 2566]. Although rotatio n about the C(2)-C(15) bond connecting the oxypyrrolinyl ring system to the carbonyl group in the pseudopeptide linkage of the tryptophanyl moiety was governed by a potential energy function having two symmetrically placed mi nima separated by +/- 42 degrees and a barrier height equivalent to only 2. 5 kJ/mol, the spin label exhibited preferred occupancy of the -42 degrees c onformer, in direct agreement with spectroscopic studies. The excellent agr eement observed between molecular dynamics and spectroscopically derived re sults provides a firm base for further applications of the force-field para meter set of this spin label for investigation of macromolecular structure and conformational flexibility through electron magnetic resonance methods. (C) 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1113-1123, 2001.