The use of time-dependent restraints in molecular simulation in order to generate a conformational ensemble for molecules that is in accordance with measured ensemble averages for particular observable quantities is investigated. Using a model system consisting of liquid butane and the cyclic peptide antamanide the reproduction of particular average 3 J-coupling constant values in a molecular dynamics simulation is analysed. It is shown that the multiple-valuedness and the sizeable gradients of

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... the Karplus curve relating 3 J-coupling constants measured in NMR experiments to the corresponding torsional-angle values cause severe problems when trying to restrain a 3 J-coupling constant to a value close to the extrema of the Karplus curve. The introduction of a factor oscillating with time into the restraining penalty function alleviates this problem and enhances the restrained conformational sampling.