Fatty acid synthases are dynamic ensembles of enzymes that can efficiently biosynthesize long hydrocarbon chains. Here we visualize the interaction between the Escherichia coli acyl carrier protein (AcpP) and β-ketoacyl-ACP-synthase I (FabB) using X-ray crystallography, NMR, and MD simulations. We leveraged this structural information to alter lipid profiles in vivo and provide a molecular basis for how protein-protein interactions can regulate the fatty acid profile in E. coli. The E. coli fatty acid synthase (FAS) produces fatty acids through an iterative cycle via the

It has been argued that the stacking of adenyl groups in water must be driven primarily by electrostatic interactions, based upon NMR data showing stacking for two adenyl groups joined by a 3-atom linker but not for two naphthyl groups joined by the same linker. In contrast, theoretical work has suggested that adenine stacking is driven primarily by nonelectrostatic forces, and that electrostatic interactions actually produce a net repulsion between adenines stacking in water. The present study provides evidence that the experimental data for the 3-atom-linked bis-adenyl and bis-naphthyl compounds are consistent with the theory indicating that nonelectrostatic interactions drive adenine stacking. First, a theoretical conformational analysis is found to reproduce the observed ranking of the stacking tendencies of the compounds studied experimentally. A geometric analysis identifies two possible reasons, other than stronger electrostatic interactions, why the 3-atom-linked bis-adenyl compounds should stack more than the bis-naphthyl compounds. First, stacked naphthyl groups tend to lie further apart than stacked adenyl groups, based upon both quantum calculations and crystal structures. This may prevent the bis-naphthyl compound from stacking as extensively as the bis-adenyl compound. Second, geometric analysis shows that more stacked conformations are sterically accessible to the bis-adenyl compound than to the bis-naphthyl compound because the linker is attached to the sides of the adenyl groups, but to the ends of the naphthyl groups. Finally, ab initio quantum mechanics calculations and energy decompositions for relevant conformations of adenine and naphthalene dimers support the view that stacking in these compounds is driven primarily by nonelectrostatic interactions. The present analysis illustrates the importance of considering all aspects of a molecular system when interpreting experimental data, and the value of computer models as an adjunct to chemical intuition.

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This paper uses a recently developed computer model to study the energetics of solvent-exposed salt-bridges. The model uses the "mining minima" method to compute conformational free energies with the CHARMm empirical force and the generalized Born solvation model. Satisfactory agreement is obtained in comparison with the measured binding affinities of ion pairs in solution and with the salt-bridge energetics deduced from studies of salt-bridges in helical peptides. The calculations suggest that stabilizing charge-charge interactions in helical peptides do not require well-defined salt-bridge conformations. This is in agreement with crystallographic studies of charge pairs added to T4 lysozyme by site-directed mutagenesis. The computer model is also used to make a testable prediction that arginine and phosphotyrosine residues in an (i, i + 4) relationship will form a particularly strong salt-bridge in helical peptides. The biological implications of these results are discussed.