282 research outputs found
ORGANIZING FORCES AND CONFORMATIONAL ACCESSIBILITY IN THE UNFOLDED STATE OF PROTEINS
For over fifty years, the unfolded state of proteins had been thought to be
featureless and random. Experiments by Tanford and Flory confirmed that unfolded
proteins possessed the same dimensions as those predicted of a random flight chain in
good solvent. In the late eighties and early nineties, however, researchers began to notice
structural trends in unfolded proteins. Some experiments showed that the unfolded state
was very similar to the native state, while others indicated a conformational preference
for the polyproline II helix in unfolded proteins. As a result, a paradox developed. How
can unfolded proteins be both random and nonrandom at the same time?
Current experiments and most theoretical simulations cannot characterize the
unfolded state in high detail, so we have used the simplified hard sphere model of
Richards to address this question. By modeling proteins as hard spheres, we can not only
determine what interactions are important in the unfolded state of proteins, but we can
address the paradox directly by investigating whether nonrandom behavior is in conflict
with random coil statistics.
Our simulations identify hundreds of disfavored conformations in short peptides,
each of which proves that unfolded proteins are not at all random. Some interactions are
important for the folded state of proteins as well. For example, we find that an α-helix
cannot be followed directly by a β-strand because of steric considerations. The
interactions outlined here limit the conformational possibilities of an unfolded protein far
beyond what would be expected for a random coil. For a 100-residue protein, we find
that approximately 9 orders of magnitude of conformational freedom are lost because of
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local chain organization alone. Furthermore, we show that the existence of this
organization is compatible with random coil statistics.
Although our simulations cannot settle the controversy surrounding the unfolded
state, we can conclude that new methods of characterizing the unfolded state are needed.
Since unfolded proteins are not random coils, the methods developed for describing
random coils cannot adequately describe the complexities of this diverse structural
ensemble
1928 Ruby Yearbook
A digitized copy of the 1928 Ruby, the Ursinus College yearbook.https://digitalcommons.ursinus.edu/ruby/1030/thumbnail.jp
Unstructured intermediate states in single protein force experiments
Recent single-molecule force measurements on single-domain proteins have
highlighted a three-state folding mechanism where a stabilized intermediate
state (I) is observed on the folding trajectory between the stretched state and
the native state. Here we investigate on-lattice protein-like heteropolymer
models that lead to a three-state mechanism and show that force experiments can
be useful to determine the structure of I. We have mostly found that I is
composed of a core stabilized by a high number of native contacts, plus an
unstructured extended chain. The lifetime of I is shown to be sensitive to
modifications of the protein that spoil the core. We then propose three types
of modifications--point mutations, cuts, and circular permutations--aiming at:
(1) confirming the presence of the core and (2) determining its location,
within one amino acid accuracy, along the polypeptide chain. We also propose
force jump protocols aiming to probe the on/off-pathway nature of I.Comment: 10 page
\u3csup\u3e1\u3c/sup\u3eH, \u3csup\u3e15\u3c/sup\u3eN, and \u3csup\u3e13\u3c/sup\u3eC Chemical Shift Assignments of the Regulatory Domain of Human Calcineurin
Calcineurin (CaN) plays an important role in T-cell activation, cardiac system development and nervous system function. Previous studies have demonstrated that the regulatory domain (RD) of CaN binds calmodulin (CaM) towards the N-terminal end. Calcium-loaded CaM activates the serine/threonine phosphatase activity of CaN by binding to the RD, although the mechanistic details of this interaction remain unclear. It is thought that CaM binding at the RD displaces the auto-inhibitory domain (AID) from the active site of CaN, activating phosphatase activity. In the absence of calcium-loaded CaM, the RD is disordered, and binding of CaM induces folding in the RD. In order to provide mechanistic detail about the CaM–CaN interaction, we have undertaken an NMR study of the RD of CaN. Complete 13C, 15N and 1H assignments of the RD of CaN were obtained using solution NMR spectroscopy. The backbone of RD has been assigned using a combination of 13C-detected CON-IPAP experiments as well as traditional HNCO, HNCA, HNCOCA and HNCACB-based 3D NMR spectroscopy. A 15N-resolved TOCSY experiment has been used to assign Hα and Hβ chemical shifts
BriX: a database of protein building blocks for structural analysis, modeling and design
High-resolution structures of proteins remain the most valuable source for understanding their function in the cell and provide leads for drug design. Since the availability of sufficient protein structures to tackle complex problems such as modeling backbone moves or docking remains a problem, alternative approaches using small, recurrent protein fragments have been employed. Here we present two databases that provide a vast resource for implementing such fragment-based strategies. The BriX database contains fragments from over 7000 non-homologous proteins from the Astral collection, segmented in lengths from 4 to 14 residues and clustered according to structural similarity, summing up to a content of 2 million fragments per length. To overcome the lack of loops classified in BriX, we constructed the Loop BriX database of non-regular structure elements, clustered according to end-to-end distance between the regular residues flanking the loop. Both databases are available online (http://brix.crg.es) and can be accessed through a user-friendly web-interface. For high-throughput queries a web-based API is provided, as well as full database downloads. In addition, two exciting applications are provided as online services: (i) user-submitted structures can be covered on the fly with BriX classes, representing putative structural variation throughout the protein and (ii) gaps or low-confidence regions in these structures can be bridged with matching fragments
Empirical Potential Function for Simplified Protein Models: Combining Contact and Local Sequence-Structure Descriptors
An effective potential function is critical for protein structure prediction
and folding simulation. Simplified protein models such as those requiring only
or backbone atoms are attractive because they enable efficient
search of the conformational space. We show residue specific reduced discrete
state models can represent the backbone conformations of proteins with small
RMSD values. However, no potential functions exist that are designed for such
simplified protein models. In this study, we develop optimal potential
functions by combining contact interaction descriptors and local
sequence-structure descriptors. The form of the potential function is a
weighted linear sum of all descriptors, and the optimal weight coefficients are
obtained through optimization using both native and decoy structures. The
performance of the potential function in test of discriminating native protein
structures from decoys is evaluated using several benchmark decoy sets. Our
potential function requiring only backbone atoms or atoms have
comparable or better performance than several residue-based potential functions
that require additional coordinates of side chain centers or coordinates of all
side chain atoms. By reducing the residue alphabets down to size 5 for local
structure-sequence relationship, the performance of the potential function can
be further improved. Our results also suggest that local sequence-structure
correlation may play important role in reducing the entropic cost of protein
folding.Comment: 20 pages, 5 figures, 4 tables. In press, Protein
Blink and you'll miss it: The role of blinking in the perception of magic tricks
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed.Magicians use several techniques to deceive their audiences, including, for example, the misdirection of attention and verbal suggestion. We explored another potential stratagem, namely the relaxation of attention. Participants watched a video of a highly skilled magician whilst having their eye-blinks recorded. The timing of spontaneous eye-blinks was highly synchronized across participants. In addition, the synchronized blinks frequency occurred immediately after a seemingly impossible feat, and often coincided with actions that the magician wanted to conceal from the audience. Given that blinking is associated with the relaxation of attention, these findings suggest that blinking plays an important role in the perception of magic, and that magicians may utilize blinking and the relaxation of attention to hide certain secret actions.Peer reviewedFinal Published versio
Magic in the machine: a computational magician's assistant
A human magician blends science, psychology and performance to create a magical effect. In this paper we explore what can be achieved when that human intelligence is replaced or assisted by machine intelligence. Magical effects are all in some form based on hidden mathematical, scientific or psychological principles; often the parameters controlling these underpinning techniques are hard for a magician to blend to maximise the magical effect required. The complexity is often caused by interacting and often conflicting physical and psychological constraints that need to be optimally balanced. Normally this tuning is done by trial and error, combined with human intuitions. Here we focus on applying Artificial Intelligence methods to the creation and optimisation of magic tricks exploiting mathematical principles. We use experimentally derived data about particular perceptual and cognitive features, combined with a model of the underlying mathematical process to provide a psychologically valid metric to allow optimisation of magical impact. In the paper we introduce our optimisation methodology and describe how it can be flexibly applied to a range of different types of mathematics based tricks. We also provide two case studies as exemplars of the methodology at work: a magical jigsaw, and a mind reading card trick effect. We evaluate each trick created through testing in laboratory and public performances, and further demonstrate the real world efficacy of our approach for professional performers through sales of the tricks in a reputable magic shop in London
Surface Plasmon Resonance, Formation Mechanism, and Surface Enhanced Raman Spectroscopy of Ag+-Stained Gold Nanoparticles
A series of recent works have demonstrated the spontaneous Ag+ adsorption onto gold surfaces. However, a mechanistic understanding of the Ag+ interactions with gold has been controversial. Reported herein is a systematic study of the Ag+ binding to AuNPs using several in-situ and ex-situ measurement techniques. The time-resolved UV-vis measurements of the AuNP surface plasmonic resonance revealed that the silver adsorption proceeds through two parallel pseudo-first order processes with a time constant of 16(±2) and 1,000(±35) s, respectively. About 95% of the Ag+ adsorption proceeds through the fast adsorption process. The in-situ zeta potential data indicated that this fast Ag+ adsorption is driven primarily by the long-range electrostatic forces that lead to AuNP charge neutralization, while the time-dependent pH data shows that the slow Ag+ binding process involves proton-releasing reactions that must be driven by near-range interactions. These experimental data, together with the ex-situ XPS measurement indicates that adsorbed silver remains cationic, but not as a charged-neutral silver atom proposed by the anti-galvanic reaction mechanism. The surface-enhanced Raman activities of the Ag+-stained AuNPs are slightly higher than that for AuNPs, but significantly lower than that for the silver nanoparticles (AgNPs). The SERS feature of the ligands on the Ag+-stained AuNPs can differ from that on both AuNPs and AgNPs. Besides the new insights to formation mechanism, properties, and applications of the Ag+-stained AuNPs, the experimental methodology presented in this work can also be important for studying nanoparticle interfacial interactions
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