Nucleotide-Induced Conformational Dynamics in ABC Transporters from Structure-Based Coarse Grained Modeling

Abstract

ATP-binding cassette (ABC) transporters are integral membrane proteins which mediate the exchange of diverse substrates across membranes powered by ATP molecules. Our understanding of their activity is still hampered since the conformational dynamics underlying the operation of such proteins cannot yet be resolved in detailed molecular dynamics studies. Here a coarse grained model which allows to mimic binding of nucleotides and follow subsequent conformational motions of full-length transporter structures in computer simulations is proposed and implemented. To justify its explanatory quality, the model is first applied to the maltose transporter system for which multiple conformations are known and we find that the model predictions agree remarkably well with the experimental data. For the MalK subunit the switching from open to the closed dimer configuration upon ATP binding is reproduced and, moreover, for the full-length maltose transporter, progression from inward-facing to the outward-facing state is correctly obtained. For the heme transporter HmuUV, for which only the free structure could yet be determined, the model was then applied to predict nucleotide-induced conformational motions. Upon binding of ATP-mimicking ligands the structure changed from a conformation in which the nucleotide-binding domains formed an open shape, to a conformation in which they were found in tight contact, while, at the same time, a pronounced rotation of the transmembrane domains was observed. This finding is supported by normal mode analysis, and, comparison with structural data of the homologous vitamin B 12 transporter BtuCD suggests that the observed rotation mechanism may contribute a common functional aspect for this class of ABC transporters. Although in HmuuV noticeable rearrangement of essential transmembrane helices was detected, there are no indications from our simulations that ATP binding alone may facilitate propagation of substrate molecules in this transporter. Possible explanations are discussed in the light of currently debated transport scenarios of ABC transporters.

Designed Elastic Networks: Models of Complex Protein Machinery

“…Related to those aspects, we remark that, in a number of previous studies, we have shown that the relaxation dynamics in the elastic networks of protein machines and motors is effectively reduced to low-dimensional attractive bundles in the conformation space, and corresponds to well-defined, ordered domain motions [ 9 , 10 , 11 , 12 , 16 ]. We concluded that this property is likely the result of biological evolution, and it ensures that protein machines and motors can robustly execute the same intrinsic conformational motions in each operation cycle.…”

“…Despite obvious simplifications, such models can reproduce conformational fluctuations in proteins, and, remarkably, normal modes of elastic networks have been shown to be able to describe even the large-amplitude motions related to ATP binding and hydrolysis in various molecular machines and motors (e.g., [ 6 , 7 , 8 ]). Moreover, in several previous studies, protein elastic networks have been considered as dynamical systems, and conformational dynamics in response to external forcing has been probed in order to investigate functional mechanochemical motions in protein machines [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Are specialised ABC transporters responsible for the circularisation of type I circular bacteriocins?

“…This also showed ADP molecules bound to the Gly-X-X-Gly-X-Gly-Lys-Thr/Ser ATP/GTP binding motif. These ABC transporters exist functionally as dimers [57, 58] as seen in Figure 2. Existing as a dimer may allow the SED triad to be in close enough proximity, given they are all found within the main groove of the structure.…”

Design of Elastic Networks with Evolutionary Optimized Long-Range Communication as Mechanical Models of Allosteric Proteins

“…Previously, the relaxational elastic-network approach employed in this study was already applied to model ATP-related dynamics in protein machines and to investigate allosteric coupling ( 35 , 36 , 45 ). Whereas in those studies allosteric coupling was only qualitatively discussed, the approach presented here may generally be applied in structure-based modeling and help in understanding important mechanistic aspects of protein allostery.…”