AcrB, a homotrimer, is the pivotal part of a multidrug efflux pump. A "functionally rotating" picture has been proposed for the drug transport by AcrB, but its mechanism remains unresolved. Here, we investigate the energetics of the whole functional rotation cycle using our theoretical methods. We find that the packing efficiency of AcrB is ununiform, and this ununiformity plays imperative roles primarily through the solvent-entropy effect. When a proton binds to or dissociates from a protomer, the packing properties of this protomer and its two interfaces are perturbed overall in the direction that the solvent translational entropy is lowered. The packing properties of the other two protomers are then reorganized with the recovery or maintenance of closely packed interfaces, so that the solvent-entropy loss can be compensated. The functional structural change by an isolated protomer would cause a seriously large free-energy increase. By forming a trimer, any free-energy increase caused by a protomer is always canceled out by the free-energy decrease brought by the other two protomers via the mechanism mentioned above. The functional structural rotation is thus accomplished using the free-energy decrease arising from the transfer of only a single proton per cycle. The similarities to F1-ATPase are also discussed.
Insertion and release of a solute into and from a cylindrical vessel comprising biopolymers is a fundamental function in biological systems. In earlier works, we reported that the solvent-entropy (SE) effect plays imperative roles for insertion. Here we show that release is also achievable by the SE effect: The solute can be moved from an entrance at one end of the vessel to an exit at the other end using a continuous variation of the vessel geometry. Since the SE effect is rather insensitive to the solute-solvent affinity, our result may provide a clue to the "multidrug efflux" of TolC.
We show how to characterize the native-structure models of a protein using our free-energy function F which is based on hydration thermodynamics. Ubiquitin is adopted as an example protein. We consider models determined by the X-ray crystallography and two types of NMR model sets. A model set of type 1 comprises candidate models for a fixed native structure, and that of type 2 forms an ensemble of structures representing the structural variability of the native state. In general, the X-ray models give lower F than the NMR models. There is a trend that, as a model deviates more from the model with the lowest F among the X-ray models, its F becomes higher. Model sets of type 1 and those of type 2, respectively, exhibit two different characteristics with respect to the correlation between the deviation and F. It is argued that the total amount of constraints such as NOEs effectively taken into account in constructing the NMR models can be examined by analyzing the behavior of F. We investigate structural characteristics of the models in terms of the energetic and entropic components of F which are relevant to intramolecular hydrogen bonding and to backbone and side-chain packing, respectively.
A newly synthesized small molecule, KTT‐1, exhibits kinetically selective inhibition of histone deacetylase 2, HDAC2, over its homologous enzyme, HDAC1. KTT‐1 is hard to be released from the HDAC2/KTT‐1 complex, compared to the HDAC1/KTT‐1 complex and the residence time of KTT‐1 in HDAC2 is longer than that in HDAC1. To explore the physical origin of this kinetic selectivity, we performed replica‐exchange umbrella sampling molecular dynamics simulations for formation of both complexes. The calculated potentials of mean force suggest that KTT‐1 is stably bound to HDAC2 and that it is easily disassociated from HDAC1. In the direct vicinity of the KTT‐1 binding site in both enzymes, there exists a conserved loop consisting of four consecutive glycine residues (Gly304‐307 for HDAC2; Gly299‐302 for HDA1). The difference between the two enzymes comes from a single un‐conserved residue behind this loop, namely, Ala268 in HDAC2 and Ser263 in HDAC1. The Ala268 contributes to the tight binding of KTT‐1 to HDAC2 by the linear orientation of Ala268, Gly306, and one carbon atom in KTT‐1. On the other hand, Ser263 cannot stabilize the binding of KTT‐1 to HDAC1, because it is relatively further away from the glycine loop and because the directions of the two forces are not in line.
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