Molecular Dynamics Reveals Drug Target Mechanisms in L. pneumophila’s T4SS

Legionella pneumophila is a gram-negative bacterial pathogen that causes several diseases, notably the severe form of pneumonia known as Legionnaires' Disease. While the Type IV Secretion System (T4SS) is known to be critical in the infection process, little is known about how it functions on a molecular level. Using a computational model of the T4SS, we have run molecular dynamics simulations showing that it is feasible, both energetically and structurally, for effector proteins to push open the 16 member polymer protein (DotG) that extends through the outer membrane. These mechanistic insights suggest that the DotG protein is a key component in the infection cycle. This, combined with its convenient location in the outer membrane, makes DotG a very promising target for structure-based drug design to combat Legionnaires' Disease.