Ribonucleotide Reductase (RNR) is an enzyme in charge of reducing ribonucleotides to deoxyribonucleotides (dNDP’s), precursors in DNA synthesis. Human ribonucleotide reductase (HRR) is a well established target in cancer therapies. HRR is a very versatile enzyme able to catalyze four different substrates, to do so it developed a highly sophisticated allosteric regulation system. Regulation in HRR occurs in subunit R1 that contains two allosteric sites and the catalytic site. HRR is a dimer in its minimal active form and this is driven by the binding of two effectors located in the interface of each monomer. These effectors can be ATP, dATP, dGTP or dTTP and they drive specificity for different NDP substrates. Either ATP or dATP also bind to the activity site and define overall regulation in HRR, while ATP increases activity, dATP switches off the enzyme. It’s not well understood whether the difference in activity caused by ATP/dATP binding is due to the difference in stability of the hexamers formed when each molecule binds to the activity site or crosstalk between the three sites. In the Roitberg group, we addressed this question by studying protein dynamics using tools from the AMBER 16 GPU package such as Gaussian accelerated Molecular Dynamics (GaMD) in the HRR dimer and steeredMD in the HRR hexamer. GaMD performed on the dimer with a specific substrate/effector and with the activity site empty or bound to ATP or dATP allowed us to recognize different conformations of HRR not observed before. Giving insight into specific domains and residues in the protein that govern communication within sites and regulate overall activity. SteeredMD applied on the HRR hexamer with ATP or dATP bound to the activity site revealed differences in hexamer stability allowing us to determine specific interactions that cause these discrepancies.

Determining allosteric regulation of human ribonucleotide reductase by detecting conformational changes and establishing oligomer stability using computational tools

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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