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Allosteric sodium in the helix bundle of a G protein-coupled receptor (GPCR) can modulate the receptor activation on the intracellular side. This phenomenon has confounded the GPCR community for decades. In this work, we present a theoretical model that reveals the mechanism of the allosteric modulation induced by sodium in the δ-opioid receptor. We found that the allosteric sodium ion exploits a distinct conformation of the key residue Trp2746.48 to propagate the modulation to helices 5 and 6…

We present a maximum-caliber method for inferring transition rates of a Markov state model (MSM) with perturbed equilibrium populations given estimates of state populations and rates for an unperturbed MSM. It is similar in spirit to previous approaches, but given the inclusion of prior information, it is more robust and simple to implement. We examine its performance in simple biased diffusion models of kinetics and then apply the method to predicting changes in folding rates for several high…

Apoptosis-inducing factor (AIF) is critical for mitochondrial respiratory complex biogenesis and for mediating necroptotic parthanatos; these functions are seemingly regulated by enigmatic allosteric switching driven by NADH charge-transfer complex (CTC) formation. Here, we define molecular pathways linking AIF’s active site to allosteric switching regions by characterizing dimer-permissive mutants using small-angle X-ray scattering (SAXS) and crystallography and by probing AIF-CTC communicati…

Related Articles Training and Validation of a Liquid-Crystalline Phospholipid Bilayer Force Field. J Chem Theory Comput. 2016 Dec 13;12(12):5960-5967 Authors: McKiernan KA, Wang LP, Pande VS Abstract We present a…

Small molecule distribution coefficients between immiscible nonaqueuous and aqueous phases-such as cyclohexane and water-measure the degree to which small molecules prefer one phase over another at a given pH. As distribution coefficients capture both thermodynamic effects (the free energy of transfer between phases) and chemical effects (protonation state and tautomer effects in aqueous solution), they provide an exacting test of the thermodynamic and chemical accuracy of physical models with…