Biomolecular structure refinement based on adaptive restraints using local-elevation simulation

Introducing experimental values as restraints into molecular dynamics (MD) simulation to bias the values of particular molecular properties, such as nuclear Overhauser effect intensities or distances, dipolar couplings, ³ J-coupling constants, chemical shifts or crystallographic structure factors, towards experimental values is a widely used structure refinement method. Because multiple torsion angle values ϕ correspond to the same ³ J-coupling constant and high-energy barriers are separating those, restraining ³ J-coupling constants remains difficult. A method to adaptively enforce restraints using a local elevation (LE) potential energy function is presented and applied to ³ J-coupling constant restraining in an MD simulation of hen egg-white lysozyme (HEWL). The method succesfully enhances sampling of the restrained torsion angles until the 37 experimental ³ J-coupling constant values are reached, thereby also improving the agreement with the 1,630 experimental NOE atom–atom distance upper bounds. Afterwards the torsional angles ϕ are kept restrained by the built-up local-elevation potential energies.