The tunnel region at triosephosphate isomerase (TIM)'s dimer interface, distant from its catalytic site, is a target site for certain benzothiazole derivatives that inhibit TIM's catalytic activity in Trypanosoma cruzi, the parasite that causes Chagas disease. We performed multiple 100-ns molecular-dynamics (MD) simulations and elastic network modeling (ENM) on both apo and complex structures to shed light on the still unclear inhibitory mechanism of one such inhibitor, named bt10. Within the time frame of our MD simulations, we observed stabilization of aromatic clusters at the dimer interface and enhancement of intersubunit hydrogen bonds in the presence of bt10, which point to an allosteric effect rather than destabilization of the dimeric structure. The collective dynamics dictated by the topology of TIM is known to facilitate the closure of its catalytic loop over the active site that is critical for substrate entrance and product release. We incorporated the ligand's effect on vibrational dynamics by applying mixed coarse-grained ENM to each one of 54,000 MD snapshots. Using this computationally efficient technique, we observed altered collective modes and positive shifts in eigenvalues due to the constraining effect of bt10 binding. Accordingly, we observed allosteric changes in the catalytic loop's dynamics, flexibility, and correlations, as well as the solvent exposure of catalytic residues. A newly (to our knowledge) introduced technique that performs residue-based ENM scanning of TIM revealed the tunnel region as a key binding site that can alter global dynamics of the enzyme.
RESPEC is a new framework that introduces residue specificity into elastic network modeling (ENM) to successfully render intact protein-ligand complexes as well as apo proteins. This framework establishes a broader application of coarse-graining idea via describing (i) a coarse-grained residue/node through its heavy atoms as virtual nodes, (ii) an effective B-factor for such a node, directly obtained from the experimental data, and (iii) a node-node interaction by a cumulative distance-dependent force constant. RESPEC improves the level of correlations with B-factors after optimizing the parameters of the model. In the absence of ligands, the mean correlations exceed 0.72, which is higher than the classical ENM results, based on a diverse set of proteins. Global modes satisfactorily describe the conformational transitions for apo structures. When the ligands are included at atomistic resolution in RESPEC calculations, mean correlation values exceed 0.9 over the same data set.
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