In Silico Exploration of Alternative Conformational States of VDAC

VDAC (Voltage-Dependent Anion-selective Channel) is the primary metabolite pore in the mitochondrial outer membrane (OM). Atomic structures of VDAC, consistent with its physiological open state, are beta-barrels formed by 19 transmembrane (TM) beta-strands and an N-terminal segment (NTERM) that folds inside the pore lumen. However, structures are lacking for VDAC's partially closed states. To provide clues about possible VDAC conformers, we used the RoseTTAFold neural network to predict structures for human and fungal VDAC sequences modified to mimic removal from the pore wall or lumen of cryptic domains, i.e., segments buried in atomic models yet accessible to antibodies in OM-bound VDAC. Predicted in vacuo structures for full-length VDAC sequences are 19-strand beta-barrels similar to atomic models, but with weaker H-bonding between TM strands and reduced interactions between NTERM and the pore wall. Excision of combinations of cryptic subregions yields beta-barrels with smaller diameters, wide gaps between N- and C-terminal beta-strands, and in some cases disruption of the beta-sheet (associated with strained backbone H-bond registration). Tandem repeats of modified VDAC sequences also were explored, as was domain swapping in monomer constructs. Implications of the results for possible alternative conformational states of VDAC are discussed.

Automated summary

VDAC is the main metabolite pore in the mitochondrial outer membrane with open and partially closed states. By predicting structures, we found that modified VDAC sequences can exhibit different conformational states, providing clues for understanding alternative structures of VDAC.