Edward Lyman

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Functioning as key players in cellular regulation of membrane curvature, BAR domain proteins bend bilayers and recruit interaction partners through poorly understood mechanisms. Using electron cryomicroscopy, we present reconstructions of full-length endophilin and its N-terminal N-BAR domain in their membrane-bound state. Endophilin lattices expose large(More)
There are several examples of membrane-associated protein domains that target curved membranes. This behavior is believed to have functional significance in a number of essential pathways, such as clathrin-mediated endocytosis, which involve dramatic membrane remodeling and require the recruitment of various cofactors at different stages of the process.(More)
We present a method to parameterize heterogeneous elastic network models (heteroENMs) of proteins to reproduce the fluctuations observed in atomistic simulations. Because it is based on atomistic simulation, our method allows the development of elastic coarse-grained models of proteins under different conditions or in different environments. The method is(More)
Although atomistic simulations of proteins and other biological systems are approaching microsecond timescales, the quality of simulation trajectories has remained difficult to assess. Such assessment is critical not only for establishing the relevance of any individual simulation but also in the extremely active field of developing computational methods.(More)
The function of G-protein-coupled receptors is tightly modulated by the lipid environment. Long-timescale molecular dynamics simulations (totaling approximately 3 mus) of the A(2A) receptor in cholesterol-free bilayers, with and without the antagonist ZM241385 bound, demonstrate the instability of helix II in the apo receptor in cholesterol-poor membrane(More)
Molecular dynamics simulations reveal substructures within the liquid-ordered phase of lipid bilayers. These substructures, identified in a 10 μs all-atom trajectory of liquid-ordered/liquid-disordered coexistence (L(o)/L(d)) are composed of saturated hydrocarbon chains packed with local hexagonal order and separated by interstitial regions enriched in(More)
Assessing the convergence of a biomolecular simulation is an essential part of any careful computational investigation, because many fundamental aspects of molecular behavior depend on the relative populations of different conformers. Here we present a physically intuitive method to self-consistently assess the convergence of trajectories generated by(More)
We previously developed an algorithm, called "resolution exchange", which improves canonical sampling of atomic resolution models by swapping conformations between high- and low-resolution simulations. Here, we demonstrate a generally applicable incremental coarsening procedure and apply the algorithm to a larger peptide, met-enkephalin. In addition, we(More)
The G-protein-coupled receptors (GPCRs) are a ubiquitous family of signaling proteins of exceptional pharmacological importance. The recent publication of structures of several GPCRs cocrystallized with ligands of differing activity offers a unique opportunity to gain insight into their function. To that end, we performed microsecond-timescale simulations(More)
Annealed importance sampling assigns equilibrium weights to a nonequilibrium sample that was generated by a simulated annealing protocol [R. M. Neal, Stat. Comput. 11, 125 (2001)]. The weights may then be used to calculate equilibrium averages, and also serve as an "adiabatic signature" of the chosen cooling schedule. In this paper we demonstrate the method(More)