Application of a receptor pruning methodology to the enoyl-ACP reductase from Escherichia coli (Fabl)

Receptor pruning is an approach for achieving reasonable conformational ensemble profile in terms of time and computational resources. The purpose of this study is to reduce the size of a model structure of enoyl-acp reductase (ENR) from E. coli, FabI, to allow ligand-receptor molecular dynamic (MD) simulations to be computationally economical yet still provide meaningful binding thermodynamic data. Three reduced-size models of FabI were created by pruning away all residues greater than 12, 10 and 8 A radius. The largest ligand was docked in the active site to define the largest required receptor model. Energy minimization and MD simulations were carried out using the MOLSIM 3.2 program. ne lowest energy structure for each of receptor models from MD calculation was compared by root mean square (RMS) fit to the equivalent portion of the crystal structure of FabI. A scale-down 12 A receptor model of the enzyme FabI maintains the structural integrity of the composite parent crystal structure. The perspectives include the structure-based design of new antituberculosis agents regarding the similarity in the active site of two ENRs, FabI and InhA (M. tuberculosis).