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Modeling the molecular pathway for DHDPS-Pyruvate complex formation

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dc.contributor.advisorSanders, David
dc.contributor.committeeMemberBowles, Richard
dc.contributor.committeeMemberGrochulski, Pawel
dc.contributor.committeeMemberGrosvenor, Andrew
dc.creatorRostam Mamasani, Maziyar
dc.date.accessioned2024-09-27T18:57:43Z
dc.date.available2024-09-27T18:57:43Z
dc.date.copyright2024
dc.date.created2024-09
dc.date.issued2024-09-27
dc.date.submittedSeptember 2024
dc.date.updated2024-09-27T18:57:44Z
dc.description.abstractDihydrodipicolinate synthase (DHDPS) is a bacterial enzyme that catalyzes the condensation of pyruvate and (S)-aspartate β-semialdehyde [(S)-ASA] to create (4S)-4-hydroxy-2,3,4,5- tetrahydro-(2S)-dipicolinic acid (HTPA), which then breaks down into (S)-lysine and mesodiaminopimelate . In bacteria, such as the human pathogen Campylobacter jejuni, DHDPS is responsible for producing essential components needed for protein and bacterial cell wall synthesis. Since this enzyme is absent in humans but vital for bacterial growth, it represents a promising target for broad-spectrum antibiotics. However, existing DHDPS inhibitors have shown limited effectiveness. The fundamental processes in biology rely on the interactions between proteins and ligands, which are crucial for various functions. These interactions are intricate and often involve multiple intermediate steps before the binding is formed. In our research, we have employed computational simulations to investigate how pyruvate binds to DHDPS and to identify the intermediate states in this interaction. One aspect that has not been previously explored in inhibitor design is the dynamic nature of the interaction between DHDPS and its substrate, such as pyruvate. Through the use of molecular dynamics simulations, we have discovered that the binding of pyruvate to DHDPS goes through a transitional phase involving different residues in and around the protein’s active site. During this phase, the substrate is firmly held in place by a network of noncovalent interactions. Significantly, many of the protein residues involved in this interaction are shared among DHDPS iii enzymes from various pathogenic bacteria. This insight into the binding intermediate could potentially aid in the development of more effective broad-spectrum DHDPS inhibitors.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10388/16117
dc.language.isoen
dc.subjectDihydrodipicolinate synthase (DHDPS), pyruvate, Campylobacter jejuni, interactions between proteins and ligands, computational simulations, transitional phase
dc.titleModeling the molecular pathway for DHDPS-Pyruvate complex formation
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentChemistry
thesis.degree.disciplineChemistry
thesis.degree.grantorUniversity of Saskatchewan
thesis.degree.levelMasters
thesis.degree.nameMaster of Science (M.Sc.)

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