15,112 research outputs found
Exploration of Reaction Pathways and Chemical Transformation Networks
For the investigation of chemical reaction networks, the identification of
all relevant intermediates and elementary reactions is mandatory. Many
algorithmic approaches exist that perform explorations efficiently and
automatedly. These approaches differ in their application range, the level of
completeness of the exploration, as well as the amount of heuristics and human
intervention required. Here, we describe and compare the different approaches
based on these criteria. Future directions leveraging the strengths of chemical
heuristics, human interaction, and physical rigor are discussed.Comment: 48 pages, 4 figure
Identifying Ligand Binding Conformations of the β2-Adrenergic Receptor by Using Its Agonists as Computational Probes
Recently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, β2-adrenergic receptor (β2AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of β2AR. We show that the select ligands bind preferentially to different predicted conformers of β2AR, and identify a role of β2AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance. © 2012 Isin et al
Mechanical Unfolding of a Simple Model Protein Goes Beyond the Reach of One-Dimensional Descriptions
We study the mechanical unfolding of a simple model protein. The Langevin
dynamics results are analyzed using Markov-model methods which allow to
describe completely the configurational space of the system. Using transition
path theory we also provide a quantitative description of the unfolding
pathways followed by the system. Our study shows a complex dynamical scenario.
In particular, we see that the usual one-dimensional picture: free-energy vs
end-to-end distance representation, gives a misleading description of the
process. Unfolding can occur following different pathways and configurations
which seem to play a central role in one-dimensional pictures are not the
intermediate states of the unfolding dynamics.Comment: 10 pages, 6 figure
Importance of chirality and reduced flexibility of protein side chains: A study with square and tetrahedral lattice models
In simple models side chains are often represented implicitly (e.g., by
spin-states) or simplified as one atom. We study side chain effects using
square lattice and tetrahedral lattice models, with explicitly side chains of
two atoms. We distinguish effects due to chirality and effects due to side
chain flexibilities, since residues in proteins are L-residues, and their side
chains adopt different rotameric states. Short chains are enumerated
exhaustively. For long chains, we sample effectively rare events (eg, compact
conformations) and obtain complete pictures of ensemble properties of these
models at all compactness region. We find that both chirality and reduced side
chain flexibility lower the folding entropy significantly for globally compact
conformations, suggesting that they are important properties of residues to
ensure fast folding and stable native structure. This corresponds well with our
finding that natural amino acid residues have reduced effective flexibility, as
evidenced by analysis of rotamer libraries and side chain rotatable bonds. We
further develop a method calculating the exact side-chain entropy for a given
back bone structure. We show that simple rotamer counting often underestimates
side chain entropy significantly, and side chain entropy does not always
correlate well with main chain packing. Among compact backbones with maximum
side chain entropy, helical structures emerges as the dominating
configurations. Our results suggest that side chain entropy may be an important
factor contributing to the formation of alpha helices for compact
conformations.Comment: 16 pages, 15 figures, 2 tables. Accepted by J. Chem. Phy
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