A primary goal in molecular simulations is to modify the potential energy of a system so that properties of the simulation match experimental data. This is traditionally done through iterative cycles of simulation and reparameterization. An alternative
approach is to bias the potential energy so that the system matches experimental data. This can be done while minimally changing the underlying free energy of the molecular simulation. Current minimal biasing methods require replicas,
which can lead to unphysical dynamics and introduces new complexity: the choice of replica number and their properties. Here, we describe a new method, called experiment directed simulation that does not require replicas, converges
rapidly, can match many data simultaneously, and minimally modifies the potential. The experiment directed simulation method is demonstrated on model systems and a three-component electrolyte simulation. The theory used to derive
the method also provides insight into how changing a molecular force-field impacts the expected value of observables in simulation.