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Modeling the molecular pathway for DHDPS-Pyruvate complex formation

Date

2024-09-27

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Thesis

Degree Level

Masters

Abstract

Dihydrodipicolinate 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.

Description

Keywords

Dihydrodipicolinate synthase (DHDPS), pyruvate, Campylobacter jejuni, interactions between proteins and ligands, computational simulations, transitional phase

Citation

Degree

Master of Science (M.Sc.)

Department

Chemistry

Program

Chemistry

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