  Experiment directed simulation is a technique to minimally bias molecular
dynamics simulations to match experimentally observed results. The method
improves accuracy but does not address the sampling problem of molecular
dynamics simulations of large systems. This work combines experiment directed
simulation with both the parallel-tempering and parallel-tempering
well-tempered ensemble replica-exchange methods to enhance sampling of
experiment directed simulations. These methods are demonstrated on the GYG
tripeptide in explicit water. The collective variables biased by experiment
directed simulation are chemical shifts, where the set-points are determined by
NMR experiments. The results show that it is possible to enhance sampling with
either parallel-tempering and parallel-tempering well-tempered ensemble in the
experiment directed simulation method. This combination of methods provides a
novel approach for both accurately and exhaustively simulating biological
systems.
