Combining elastic network models and linear response theory as tool to understand the global dynamics in allosteric regulation of HCN channels

Hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN channels) play important regulatory roles in the heart and the brain. At the core of their physiological functions is an activation by negative membrane potential and its modulation by cyclic nucleotides. While recent high-resolution cryo-EM structures combined with MD simulations have provided insights into fast events in the pore, like ion permeation, block, and cation-selectivity, the mechanism of slow allosteric regulation of gating by voltage and cyclic nucleotides remains poorly understood. Since slow conformational changes in proteins are largely determined by their global dynamics, coarse-grained computational methods such as elastic network models (ENMs) and linear response theory (LRT) analyses have been used to elucidate the intrinsic collective dynamics in HCN proteins associated with cyclic nucleotide-modulated gating. In this overview, we demonstrate the good performance of coarse-grained methods in predicting long-range conformational changes in HCN channels with respect to experimentally determined conformational states in these proteins with and without bound ligand. This provides general insights into the mechanical coupling of domains in HCN channels and on how their general tectonics enables bidirectional modulation between the binding site for cyclic nucleotides in the cytosol and the distant voltage-sensitive domain in the plasma membrane-embedded part of the protein.