Exploring the A22-Bacterial Actin MreB Interaction through Molecular Dynamics Simulations.
MreB is an actin-like cytoskeleton protein that plays a vital role in the maintenance of the rod-shaped morphology of many bacteria. S-(3,4-Dichlorobenzyl) isothiourea (A22) is an antibiotic-like small molecule that perturbs the rod cell shape and has been suggested to inhibit MreB by targeting ATP hydrolysis. However, without the elucidation of the structure of the ATP-bound state of MreB in the presence of A22, the mechanism of A22 inhibition is still not clear. Here we apply conventional molecular dynamics simulations to explore the dynamics of the active site of MreB in complex with A22 and different nucleotides. We observe that hydrogen bonding between A22 and the catalytic Glu140 residue is not favored in the ATP-A22-bound state of MreB. Water dynamics analysis in the MreB active site reveals that in the presence of A22 water molecules are able to occupy positions suitable for ATP hydrolysis. Overall, our results are consistent with a mechanism in which A22 affects MreB polymerization/depolymerization dynamics in part through slowing phosphate release rather than by inhibiting ATP hydrolysis. These data can be incorporated in the design/development of the next generation of MreB inhibitors.
School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551.
Yaw
Y
Awuni
Institute of Molecular and Cell Biology , A*STAR, Biopolis, Singapore 138673.
Shimin
S
Jiang
School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551.|Institute of Molecular and Cell Biology , A*STAR, Biopolis, Singapore 138673.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 117597.|Institute of Structural Biology, Nanyang Technological University , 59 Nanyang Drive, Singapore 636921.|Lee Kong Chian School of Medicine , 50 Nanyang Avenue, Singapore 639798.
Robert C
RC
Robinson
School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, Singapore 637551.
Yuguang
Y
Mu
D000199:Actins / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry*; D016935:Caulobacter crescentus / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
D000199:Actins; D001426:Bacterial Proteins