Differential spontaneous folding of mycolic acids from Mycobacterium tuberculosis

Highlights

• Atomistic MD simulations of 3 different M. Tb. mycolic acids (MAs) are reported.

• Explicit stereochemistry is included in the modeled species.

• PCA and SOM are used for the first time with MA simulations to visualize folding.

• Keto-MAs fold more quickly and compactly than either alpha- or methoxy-MAs.

• Small changes in stereochemistry and functionality of MAs dictate macrostructure.

Abstract

Mycolic acids are structural components of the mycobacterial cell wall that have been implicated in the pathogenicity and drug resistance of certain mycobacterial species. They also offer potential in areas such as rapid serodiagnosis of human and animal tuberculosis. It is increasingly recognized that conformational behavior of mycolic acids is very important in understanding all aspects of their function. Atomistic molecular dynamics simulations, in vacuo, of stereochemically defined Mycobacterium tuberculosis mycolic acids show that they fold spontaneously into reproducible conformational groupings. One of the three characteristic mycolate types, the keto-mycolic acids, behaves very differently from either α-mycolic acids or methoxy-mycolic acids, suggesting a distinct biological role. However, subtle conformational behavioral differences between all the three mycolic acid types indicate that cooperative interplay of individual mycolic acids may be important in the biophysical properties of the mycobacterial cell envelope and therefore in pathogenicity.