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Collective protein structural transitions couple with fluctuations of their aqueous environment to enable biological function. Although decades of experiment have investigated protein-motion hy- dration couplings, atomistic details regarding global hydration structures and their transitions as- sociated with large-scale protein motions have remained elusive. This knowledge gap has hindered computer aided drug design strategies which fail to account for protein and aqueous structural transitions in a physically rigorous manor. Consequently, the detection of hidden drug binding sites hypothesized to form during rare conformational transitions has proven to be exceedingly difficult. These elusive pockets are named cryptic sites, and are of immense therapeutic value due to their ability to couple to enzymatic active sites and allosterically modulate catalytic activity. Molecular Dynamics (MD) simulations provide excellent spatial and temporal resolution to observe protein and hydration dynamics but struggle to adequately sample cryptic site formations. Over the past decade the Yang lab has worked to overcome this deficiency by developing the Orthog- onal Space Tempering (OST) enhanced sampling technique, uniquely designed to accelerate rare conformational transitions of biomolecules and their environment. The focus of this dissertation is to enrich computational drug development by understanding how collective protein motions are coupled to the aqueous environment. Towards this goal, a novel toolkit of GPU-accelerated algorithms has been developed to 1) elucidate the hydration structure enveloping proteins, 2) reveal collective protein and water structural fluctuations, and 3) map causal dynamics throughout proteins and their environment. These algorithms are first utilized on the millisecond long MD simulation of Bovine Pancreatic Trypsin Inhibitor (BPTI) performed by D. E. Shaw Research, one of the longest MD simulations performed to date. BPTI has been thoroughly investigated by biophysicists for decades and is known to harbor several buried water molecules, making it a fertile system to investigate hydration couplings. By application of our toolkit, we successfully characterize known conformational transitions of BPTI and elucidate how these motions are coupled to, and to an extent caused by, the aqueous environment. Next, OST is utilized to simulate TEM-1 β-lactamase, an enzyme that harbors a pair of cryptic sites capable of modulating the degradation of β-lactam antibiotics, making it a valuable therapeutic target in the fight against antibiotic resistance. Application of our toolkit characterizes large scale motions of TEM-1 and its aqueous environment, including expansions of the cryptic site cavities and the active site, which are connected to each other by structural hydration linkages. We then reveal immense couplings between TEM-1 and aqueous conformational transitions and investigate causal dynamics among the cryptic sites, active site, and the environment. Through the culmination of these analysis, we identify a prospective cryptic site that is allosterically linked to the active site by collective hydration fluctuations. In summary, the work presented here provides a promising foundation to enrich computational drug development strategies by understanding the intimate relationship between proteins and the aqueous environment.