We use atomistic simulations and advanced sampling to map the conformational landscapes of biomolecules (proteins, nucleic acids and their complexes) and to connect structure to function. These approaches provide a predictive framework to understand and ultimately control biomolecular flexibility, hydration, and reactivity in realistic environments relevant to biology and medicinal chemistry. Recent applications include RNA catalysis, extremophilic enzymes, allosteric regulation of proteins, DNA junctions and CO2 enzymes.