The time course of a vibrational probe is ultra-sensitive to the motions of nearby atoms, particularly those with net charges like water, which cause instantaneous fluctuations of the vibrational frequency. Two dimensional infrared spectroscopy leads to direct quantitative inferences on these solvent motions. We have utilized 2D IR spectroscopic methods to probe the dynamics of local environments of peptides and proteins at equilibrium wherein the hydrogen bond dynamics of two aromatic nitriles in methanol was investigated and the experimental parameters for utilizing nitriles as probes of solvent environments in complex biomolecules were established. Cyano-phenylalanine mutants of the M2 influenza channel were employed to assess pH induced hydration changes near the tryptophan gate that controls flow of water through the channel. A structurally less perturbative approach of utilizing isotopically substituted backbone amide vibrations to probe water structures was applied to exploring the ebb and flow of water in the M2 channel through the 2D IR spectral dynamics of the amide mode of the Gly34 residue. The 2D IR spectroscopy of Gly34 in the M2 channel revealed that the conformational equilibrium in M2 entails a change in the mobility of the channel water similar to what might be expected for phase transition from frozen to liquid water. The aforementioned approach was extended to address drug binding modes in the channel. 2D IR experiments with drug-free and drug-bound channels expose the water mobility in the channel under different drug binding conditions, which is reflected in the spectral dynamics of the Ala30 and Gly34 amides, thus revealing a functional model of drug binding in the channel that is in qualitative consistency with the model proposed from MD simulations.