An Exhaustive Search Algorithm to Aid NMR-Based Structure Determination of Rotationally Symmetric Transmembrane Oligomers.

Nuclear magnetic resonance (NMR) has been an important source of structural restraints for solving structures of oligomeric transmembrane domains (TMDs) of cell surface receptors and viral membrane proteins. In NMR studies, oligomers are assembled using inter-protomer distance restraints. But, for oligomers that are higher than dimer, these distance restraints all have two-fold directional ambiguity, and resolving such ambiguity often requires time-consuming trial-and-error calculations using restrained molecular dynamics (MD) with simulated annealing (SA). We report an Exhaustive Search algorithm for Symmetric Oligomer (ExSSO), which can perform near-complete search of the symmetric conformational space in a very short time. In this approach, the predetermined protomer model is subject to full angular and spatial search within the symmetry space. This approach, which can be applied to any rotationally symmetric oligomers, was validated using the structures of the Fas death receptor, the HIV-1 gp41 fusion protein, the influenza proton channel, and the MCU pore. The algorithm is able to generate approximate oligomer solutions quickly as initial inputs for further refinement using the MD/SA method.