The Aim Of The Present Thesis Is To Study The Formation Of Long Range Proton Transfer Pathways In Proteins Due To Side Chain Conformational Fluctuations Of Amino Acid Residues And Reorganization Of Long Time Hydration Positions Inside Proteins. The Proton Transfer Pathways In Proteins May Be Modeled As Fluctuating Hydrogen Bonded Networks With Both Short And Long-Lived Connections Between The Networked Nodes, The Latter Being Formed By Polar Protein Atoms And Water Molecules. It Is Known That These Fluctuations May Extend Over Several Decades Of Time Ranging From A Few Femtoseconds To A Few Milliseconds. In This Thesis, Several Different Theoretical Approaches Are Utilized To Detect The Proton Transfer Pathways In The Enzyme Human Carbonic Anhydrase II Formed At Long Time Scales And To Probe The Mechanism Of Key Conformational Fluctuations Contributing To The Formation Of These Pathways. Key Words: Carbonic Anhydrase, Proton Path, Hydration, Mutant, Conformational Sampling, Protein Dynamics, Transition Path. Xiii