Why OppA protein can bind sequence-independent peptides? A combination of QM/MM, PB/SA, and structure-based QSAR...

Periplasmic oligopeptide-binding protein (OppA) is the initial receptor in the ATP-binding cassette (ABC) system of bacteria, which exhibits a broad specificity in binding oligopeptides without regard to sequence. Here, we present a computational study on the structural properties and energetic landscapes of OppA protein interacting with its cognate ligands on the basis of 28 structure/affinity-known OppA-tripeptide complexes. By employing a well-designed protocol that couples the hybrid quantum mechanical/molecular mechanical (QM/MM) scheme and the sophisticated Poisson-Boltzmann/surface area (PB/SA) solvent model together to analyze and decompose the energy components associated with the OppA-peptide binding, we demonstrate that the broad specificity of OppA-recognizing peptides is originated from a series of exquisite balances between the free energy contributions from, for example, the direct nonbonded interactions and indirect desolvation effects, the main chains and side chains, and the different residue positions of the tripeptide ligands. We also show that, in a framework of structure-based quantitative structure-activity relationship (SB-QSAR) methodology, the QM/MM-PB/SA-derived energy terms could be used as a good descriptor to characterize the interaction profile of OppA with peptides and correlate pretty well with the experimentally measured affinities of the binding.