Structural and mechanistic comparison of the CMAS protein family of Mycobacterium tuberculosis.

FEDERICO OSMAN; MARCELO ADRIÁN MARTÍ; LUCAS A. DEFELIPE; ADRIAN GUSTAVO TURJANSKI

Buenos Aires

Congreso; ISCB Latin America; 2016

Asociación argentina de bioinformática y biología computacional

Cyclopropane Mycolic Acid Synthase (CMAS) protein family have a methyltransferase activity depedant on S-adenosyl-L-methionine (SAM) responsible for Mycolic acid (MA) modifications in Mtb. Each member of the family has a marked selectivity and catalyses the formation of a specific product like cyclopropanes, methyl-alcohol groups or even ether groups. The molecular determinants for this differential activities is poorly understood. In this work, we present a combined structural bioinformatics/QM-MM MD simulation approach to explain the difference in selectivity/activity in this protein family. In particular, observed changes in the nC-B4 (GxE) loop of cmaA2 prevent the binding a bicarbonate ion favoring methyl-alcohol modifications in mmaA4. On the other hand, sequence modifications in the B4-n1 (ExD) loop changes the activity towards methyl-olefin seen in mmaA1. Using the differential activity information we developed a specific diversity screening set targeting the proteins with a bicarbonate ion in their active site (cmaA1-2, pcaA, mmaA2 y umaA develop high throughput docking protocol which targets) using umaA as a reference. We used this set in a high throughput docking pipeline to search for new compounds to specifically inhibit cyclopropane synthase activity of the family. The best 20 compounds were further studied by means of Molecular Dynamic (MD) simulations and MM-PBSA.