Biophysical simulation can be an excellent complement to experimental techniques, but there are unresolved practical constraints to simulation. While computers have continued to improve, the scale of systems we wish to study has continued to increase. This has driven the use of approximate energy functions (force fields), compensating for relatively short simulations via careful structure preparation and accelerated sampling techniques. To address structure preparation, we developed the many-body dead end elimination (MB-DEE) optimizer. We first proved the MB-DEE algorithm on a set of PCNA crystal structures, and accelerated it on GPUs to optimize 472 homology models of proteins implicated in inherited deafness. Advanced physics has been clearly demonstrated to help optimize structures, and with GPU acceleration, this becomes a possibility for large numbers of structures. We also show the novel “simultaneous bookending” algorithm, which is a new approach to indirect free energy (IFE) methods. These first perform simulations under a cheaper “reference” potential, then correct the thermodynamics to a more sophisticated “target” potential, combining the speed of the reference potential with the accuracy of the target potential. Simultaneous bookending is shown as a valid IFE approach, and methods to realize speedups vs. the direct path are discussed. Finally, we are developing the Monte Carlo Orthogonal Space Random Walk (MC-OSRW) algorithm for high-performance alchemical free energy simulations, bypassing some of the difficulty in OSRW methods. This work helps prevent inaccuracies caused by simpler electrostatic models by making advanced polarizable force fields more accessible for routine simulation.