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Structural repair of mechanical defects in the Mycobacterium tuberculosis outer membrane. A molecular dynamics study
Alexey V Rozhkov1, Alexander V Vasyankin1, Ekaterina A Shirokova1
1Department of Chemistry, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, 603022, Russia.
Abstract:
The outer membrane of Mycobacterium tuberculosis plays a key role in the pathogen's resistance to environmental stress and antibiotic treatment. The structural defects of the membrane are considered as one of key potential pathways for the penetration of large molecules into the mycobacterium cell. Thus, understanding the molecular mechanisms underlying the formation and repair of defects in this membrane is important for the development of drugs with better efficacy and penetrating ability against Mycobacterium tuberculosis. In this work we used molecular dynamics simulations based on the coarse-grained Dry Martini force field to study the dynamics of membrane defect repair. The defect closing times strongly depend on their type, size, and system temperature. The fastest closing process was found for small circular holes of 3 nm diameter, which occurred within ∼1 ns at 300 K, while increasing the defect size to 6 nm resulted in closing within ∼20 ns. For the vertical fault defects, a critical height value of ∼4.85 nm was found, above which the defect closing becomes unlikely or impossible, which may determine the limitation of the membrane's ability to recover from severe mechanical damage.
Insights
Understanding how Mycobacterium tuberculosis outer membrane defects repair is key for developing new drugs. Simulations show defect closure depends on size and temperature, with smaller defects repairing faster.
Area of Science:
- Biophysics
- Microbiology
- Computational Biology
Background:
- The outer membrane of Mycobacterium tuberculosis is crucial for its survival and resistance.
- Membrane defects are potential entry points for drugs, but their repair mechanisms are poorly understood.
Purpose of the Study:
- To investigate the molecular dynamics of outer membrane defect repair in Mycobacterium tuberculosis.
- To determine factors influencing the rate and feasibility of membrane defect closure.
Main Methods:
- Coarse-grained molecular dynamics simulations using the Dry Martini force field.
- Analysis of defect closing times based on defect type, size, and temperature.
Main Results:
- Defect closing times are highly dependent on defect type, size, and temperature.
- Small circular defects (3 nm) closed within ~1 ns at 300 K, while larger defects (6 nm) took ~20 ns.
- A critical height of ~4.85 nm was identified for vertical faults, beyond which closure is unlikely.
Conclusions:
- The study provides insights into the mechanical properties and repair capabilities of the mycobacterial outer membrane.
- Findings suggest limitations on the membrane's ability to recover from significant damage.
- Understanding these dynamics is vital for designing drugs with enhanced penetration into Mycobacterium tuberculosis.
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