村田 武士

Privalov and co-workers estimated the changes in hydration enthalpy and entropy upon ubiquitin unfolding and their temperature dependences denoted by ΔHhyd(T) and ΔShyd(T), respectively, from experimentally measured enthalpies and entropies of transfer of various model compounds from gaseous phase to water. We calculate ΔHhyd(T) and ΔShyd(T) for ubiquitin by our statistical-mechanics theory where molecular and atomistic models are employed for water and protein structure, respectively. ΔHhyd(T) and ΔShyd(T) calculated are in remarkably good agreement with those estimated by Privalov and co-workers. By examining relative magnitudes and signs of the changes in a variety of constituents of ΔHhyd(T) and ΔShyd(T), we confirm that the hydrophobic effect is an essential force driving a protein to fold. Detailed and comprehensive explanations are given for our claim that the prevailing views of the hydrophobic effect are not capable of elucidating its weakening at low temperatures, whereas our updated view is. We find out problematic points of the changes in enthalpy and entropy upon protein unfolding denoted by ΔH°(T) and ΔS°(T), respectively, which are measured using the differential scanning calorimetry at low pH, suggesting a theoretical method of calculating ΔH°(T) and ΔS°(T) at pH ∼ 7.

During drug discovery, it is crucial to exclude compounds with toxic effects. The human ether-à-go-go-related gene (hERG) channel is essential for maintaining cardiac repolarization and is a critical target in drug safety evaluation due to its role in drug-induced arrhythmias. Inhibition of the hERG channel can lead to severe cardiac issues, including Torsades de Pointes tachycardia. Understanding hERG inhibition mechanisms is essential to avoid these toxicities. Several structural studies have elucidated the interactions between inhibitors and hERG. However, orientation and resolution issues have so far limited detailed insights. Here, we used digitonin to analyze the apo state of hERG, which resolved orientation issues and improved the resolution. We determined the structure of hERG bound to astemizole, showing a clear map in the pore pathway. Using this strategy, we also analyzed the binding modes of E-4031 and pimozide. These insights into inhibitor interactions with hERG may aid safer drug design and enhance cardiac safety.