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Biomolecular Dynamics and Function: A Study on Amino Acids and Enzymes


Proteins are biomolecules involved in cellular structure as well as function. These molecules are long chain polymers consisting of amino acids, which are organic compounds containing many different functional groups such as amine (−NH2) and carboxylic acids (−COOH). Actin proteins form part of the cellular structure, membrane proteins act as channels for transfer of ions, and enzymes catalyze critical cellular reactions. While structure is a well- appreciated determinant of function, the role of dynamics of proteins and solvent are less well studied. In my thesis work, I have studied the statistical fluctuations and dynamics of the basic amino acids in water and up to the full complexity of enzymes. The combination of experimental and computational techniques is a powerful combination for obtaining insight into dynamical events. I have used force-field based classical molecular dynamics simulations using an advanced polarizable force field to study the behaviour of these biomolecules in so- lution and have simulated experimental observables to understand conformational motions.

In the first part of my thesis, I have characterized the dynamical modes of a basic pro- tein unit - a single zwitterionic amino acid in solution - to make quantitative comparisons to the low frequency Terahertz (THz) absorption spectra. An analysis protocol for decom- posing the THz absorption spectrum has been previously developed for analyzing zwitterion simulations performed using ab-initio molecular dynamics (AIMD). In this work we extend the analysis method to simulations performed by force field molecular dynamics, which are computationally far less intensive, and setting the stage for decomposing the THz spectra for larger proteins that are not affordable by AIMD. We also show that the main impact of the solvation on the dynamical modes of zwitterions comes from the first solvation shell around the zwitterion only, and presence of waters further out does not affect the dynamics of these molecules significantly.

In the second part of my thesis work, I have explored the role of statistical fluctuations of solvation for artificial enzymes - which have poor activity - and have evaluated how the entropic features change upon mutation through laboratory directed evolution in which the enzymes show much greater activity. I have used two Kemp Eliminases (KE07 and KE70) and show that the active sites of these two enzymes have starkly contrasting interactions with solvent. KE07 incorporates the water into the active site to enhance the catalysis of the Kemp Elimination reaction while KE70 creates a strong hydrophobic pocket leading to the catalysis being driven entirely by the protein residues at the active site. Different entropic species of waters based on their vibrational dynamics are identified, and we observe varying behaviour of waters between mutants, as well as with the presence of the ligand.

In the final part of my thesis, I have looked at the dynamical correlations between residues in KE07 and have evaluated how the dynamical correlations change upon mutation through laboratory directed evolution. In particular, I have characterized the residue-residue inter- actions where we find that there is correlated motion between surface loops in KE07, which potentially could modulate access of the ligand to the active site of the enzyme; we observe that the binding of the ligand increases the correlation between the residues of the protein in the higher performing variants of the enzyme.

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