Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these enzymes themselves. Here, we show that HDAC8 is allosterically regulated by shifts in populations between exchanging states. An inactive state is identified, which is stabilised by a range of mutations and resembles a sparsely-populated state in equilibrium with active HDAC8. Computational models show that the inactive and active states differ by small changes in a regulatory region that extends up to 28 Å from the active site. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, thus suggesting a general mechanism. The presented results pave the way for the development of allosteric HDAC inhibitors and regulators to improve the therapy for several disease states.

A framework is presented to derive the conformational sampling of isoleucine side chains from nuclear magnetic resonance 13C chemical shifts.

the operation of a range of bioelectronic devices, [1][2][3] such as organic electrochemical transistors (OECTs), [4][5][6] batteries, [7] and supercapacitors. [6] They have inherent advantages over traditional organic semiconductors for these electrochemical applications, [4,[8][9][10] in particular their ability to operate with an aqueous electrolyte. [11,12] Exchanging a traditional alkyl-based side chain for a glycol-based hydrophilic side chain has been widely adopted as a strategy for increasing uptake of water and ions in OMIECs, and subsequently increasing their capacitance. [5,7,[13][14][15] Whilst polythiophenes bearing long alkyl side chains are often reported to pack with interdigitating side chains [16][17][18][19][20][21][22] and π-stacks that are either straight or lightly tilted [17,20,[22][23][24] (see Figure S1, Supporting Information for backbone packing motifs referred to in this study), little is known about glycolated OMIEC packing, despite the chain packing being critical to both electronic and ionic transport. [21,[25][26][27][28] Experimental studies have suggested that glycolated OMIECs adopt smaller π-stack distances than their alkylated counterparts. [5,29] As well as solid-state packing, structural characterization of OMIECs should account for their swelling behavior, Exchanging hydrophobic alkyl-based side chains to hydrophilic glycol-based side chains is a widely adopted method for improving mixed-transport device performance, despite the impact on solid-state packing and polymer-electrolyte interactions being poorly understood. Presented here is a molecular dynamics (MD) force field for modeling alkoxylated and glycolated polythiophenes. The force field is validated against known packing motifs for their monomer crystals. MD simulations, coupled with X-ray diffraction (XRD), show that alkoxylated polythiophenes will pack with a "tilted stack" and straight interdigitating side chains, whilst their glycolated counterpart will pack with a "deflected stack" and an s-bend side-chain configuration. MD simulations reveal water penetration pathways into the alkoxylated and glycolated crystals-through the π-stack and through the lamellar stack respectively. Finally, the two distinct ways triethylene glycol polymers can bind to cations are revealed, showing the formation of a metastable single bound state, or an energetically deep double bound state, both with a strong side-chain length dependence. The minimum energy pathways for the formation of the chelates are identified, showing the physical process through which cations can bind to one or two side chains of a glycolated polythiophene, with consequences for ion transport in bithiophene semiconductors.