Michael V. LeVine

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We present the dynamic mechanism of concerted motions in a full-length molecular model of the human dopamine transporter (hDAT), a member of the neurotransmitter/sodium symporter (NSS) family, involved in state-to-state transitions underlying function. The findings result from an analysis of unbiased atomistic molecular dynamics simulation trajectories(More)
Complex networks of interacting residues and microdomains in the structures of biomolecular systems underlie the reliable propagation of information from an input signal, such as the concentration of a ligand, to sites that generate the appropriate output signal, such as enzymatic activity. This information transduction often carries the signal across(More)
Solute transport across cell membranes is ubiquitous in biology as an essential physiological process. Secondary active transporters couple the unfavorable process of solute transport against its concentration gradient to the energetically favorable transport of one or several ions. The study of such transporters over several decades indicates that their(More)
In performing their biological functions, molecular machines must process and transmit information with high fidelity. Information transmission requires dynamic coupling between the conformations of discrete structural components within the protein positioned far from one another on the molecular scale. This type of biomolecular "action at a distance" is(More)
Rigid-body motions of protein secondary structure are often implicated in mechanisms of protein function. In GPCRs, evidence suggests that intracellular loop 2 (IL2) contains a segment characterized as a helix when the activated receptor triggers downstream signaling. However, neither experimental nor computational methods are readily available to assess(More)
Recent work has shown that the choice of the type and concentration of detergent used for the solubilization of membrane proteins can strongly influence the results of functional experiments. In particular, the amino acid transporter LeuT can bind two substrate molecules in low concentrations of n-dodecyl β-d-maltopyranoside (DDM), whereas high(More)
Many of the functions of transmembrane proteins involved in signal processing and transduction across the cell membrane are determined by allosteric couplings that propagate the functional effects well beyond the original site of activation. Data gathered from breakthroughs in biochemistry, crystallography, and single molecule fluorescence have established(More)
Allostery plays a fundamental role in most biological processes. However, little theory is available to describe it outside of two-state models. Here we use a statistical mechanical approach to show that the allosteric coupling between two collective variables is not a single number, but instead a two-dimensional thermodynamic coupling function that is(More)
GPCRs regulate all aspects of human physiology, and biophysical studies have deepened our understanding of GPCR conformational regulation by different ligands. Yet there is no experimental evidence for how sidechain dynamics control allosteric transitions between GPCR conformations. To address this deficit, we generated samples of a wild-type GPCR (A2AR)(More)
SUPPORTING METHODS MD Simulations LeuTPOPE/POPG: In the LeuTPOPE/POPG simulation the occluded LeuT structure [1] (PDB ID 3GJD) bound to the two sodium ions and leucine, but with the octyl-glucoside (OG) detergent molecule removed, is embedded in a bilayer membrane model composed 534 POPE and 160 POPG lipids, fully solvated in TiP3P water and 0.15 mM NaCl.(More)
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