Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics, and their biological function. Currently, it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome “collective variable” enhanced sampling protocols. Here, we describe a framework that combines ensemble MD simulations and virtual reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables a priori. We further show that eMD-VR generated pathways can be combined with Markov state models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts.