Cyclophilin A (CypA) is the well-studied member of a group of ubiquitous and evolutionarily conserved families of enzymes called peptidyl–prolyl isomerases (PPIases). These enzymes catalyze the cis-trans isomerization of peptidyl-prolyl bond in many proteins. The distinctive functional path triggered by each isomeric state of peptidyl-prolyl bond renders PPIase-catalyzed isomerization a molecular switching mechanism to be used on physiological demand. PPIase activity has been implicated in protein folding, signal transduction, and ion channel gating as well as pathological condition such as cancer, Alzheimer’s, and microbial infections. The more than five order of magnitude speed-up in the rate of peptidyl–prolyl cis–trans isomerization by CypA has been the target of intense research. Normal and accelerated molecular dynamic simulations were carried out to understand the catalytic mechanism of CypA in atomistic details. The results reaffirm transition state stabilization as the main factor in the astonishing enhancement in isomerization rate by enzyme. The ensuing intramolecular polarization, as a result of the loss of pseudo double bond character of the peptide bond at the transition state, was shown to contribute only about −1.0 kcal/mol to stabilizing the transition state. This relatively small contribution demonstrates that routinely used fixed charge classical force fields can reasonably describe these types of biological systems. The computational studies also revealed that the undemanding exchange of the free substrate between β- and α-helical regions is lost in the active site of the enzyme, where it is mainly in the β-region. The resultant relative change in conformational entropy favorably contributes to the free energy of stabilizing the transition state by CypA. The isomerization kinetics is strongly coupled to the enzyme motions while the chemical step and enzyme–substrate dynamics are in turn buckled to solvent fluctuations. The chemical step in the active site of the enzyme is therefore not separated from the fluctuations in the solvent. Of special interest is the nature of catalysis in a more realistic crowded environment, for example, the cell. Enzyme motions in such complicated medium are subjected to different viscosities and hydrodynamic properties, which could have implications for allosteric regulation and function.

G-quadruplex forming human telomere sequence (HTS) DNA, has been widely studied due to the telomere's implied role in biological processes, including cellular ageing and cancer physiology. The goal of these previous efforts has been to characterize the physiologically relevant structures and their stability and dynamics in order to develop therapeutic applications. Unfortunately, understanding the biologically relevant form of the human telomere DNA is complicated by the fact that HTS-derived sequences are highly polymorphic. To further complicate the issue, recent investigations have demonstrated the ability of "cell-like" co-solvents to alter the preferred G-quadruplex fold of HTS DNA. However, the origins of G-quadruplex structure selection, the relative contributions of crowding versus dehydration, and the possible effects of co-solvents on kinetically determined folding pathways remain unresolved. Towards answering these questions, I investigated HTS DNA G-quadruplex in extreme anhydrous and high viscosity conditions utilizing a deep eutectic solvent (DES) consisting of choline chloride and urea. Herein I report that the water-free DES supports an extremely stable parallel stranded structure, consistent with observations that diminished water activity is the main cause of structural transitions to the "parallel-propeller" form. Furthermore, my research shows that the highly viscous nature of the solvent enables significant diffusion based control over HTS g-quadruplex folding rates and topology, fully consistent with Kramers rate theory. To the best of my knowledge, this is the first example of the kinetic exploration of G-quadruplex folding utilizing high friction solvent; the results of which display a decreased intramolecular folding rate of HTS DNA to a never before encountered time scale on the order of days at physiological temperature. Moreover, I have demonstrated that the folding pathway of a G-quadruplex can be altered with increased solvent friction. These discoveries are important because they highlight the need to consider the viscosity when exploring the dynamics of human telomeres specifically drug binding and folding of G-quadruplexes in vivo where cellular viscosity has been reported to be as high as 140cP. Lastly, it appears that tuning solvent viscosity could prove useful to the continued study of G-quadruplex dynamics.