Insights into the structure of the PmrD protein with molecular dynamics simulations

Area of Science:

• Microbiology
• Structural Biology
• Biochemistry

Background:

• Gram-negative bacteria develop resistance to polymyxin B, a crucial antibiotic.
• This resistance is mediated by two-component systems (TCSs), specifically PmrA/PmrB and PhoP/PhoQ.
• PmrD is identified as the first protein linking these two TCSs.

Purpose of the Study:

• To investigate the molecular dynamics and structural stability of the PmrD protein.
• To understand the interactions contributing to PmrD's unique 3D fold.
• To explore the mobility of loops within the PmrD structure.

Main Methods:

• Molecular dynamics simulations initiated from the NMR-derived 3D structure of PmrD.
• Analysis of hydrophobic and electrostatic interactions.
• Calculation of solvent-accessible surface area.

Main Results:

• Numerous hydrophobic and electrostatic interactions were identified as key to PmrD's 3D stability.
• The mobility of the five loops connecting the six beta-strands was characterized.
• A leucine-rich hydrophobic cluster was found to significantly stabilize the protein structure.

Conclusions:

• PmrD's unique fold is stabilized by a combination of hydrophobic and electrostatic forces.
• The identified hydrophobic cluster plays a critical role in maintaining PmrD's structural integrity.
• Understanding PmrD's structure and stability provides insights into polymyxin B resistance mechanisms in Gram-negative bacteria.