scholarly journals SWOTein: a structure-based approach to predict stability Strengths and Weaknesses of prOTEINs

2021 ◽  
Author(s):  
Qingzhen Hou ◽  
Fabrizio Pucci ◽  
François Ancien ◽  
Jean-Marc Kwasigroch ◽  
Raphaël Bourgeas ◽  
...  
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Large Scale ◽  
Hydrogen Exchange ◽  
Test Cases ◽  
Energy Functions ◽  
Functional Regions ◽  
Large Scale Analysis ◽  
The Individual ◽  
Structured Proteins

Abstract Motivation Although structured proteins adopt their lowest free energy conformation in physiological conditions, the individual residues are generally not in their lowest free energy conformation. Residues that are stability weaknesses are often involved in functional regions, whereas stability strengths ensure local structural stability. The detection of strengths and weaknesses provides key information to guide protein engineering experiments aiming to modulate folding and various functional processes. Results We developed the SWOTein predictor which identifies strong and weak residues in proteins on the basis of three types of statistical energy functions describing local interactions along the chain, hydrophobic forces and tertiary interactions. The large-scale analysis of the different types of strengths and weaknesses demonstrated their complementarity and the enhancement of the information they provide. Moreover, a good average correlation was observed between predicted and experimental strengths and weaknesses obtained from native hydrogen exchange data. SWOTein application to three test cases further showed its suitability to predict and interpret strong and weak residues in the context of folding, conformational changes and protein-protein binding. In summary, SWOTein is both fast and accurate and can be applied at small and large scale to analyze and modulate folding and molecular recognition processes. Availability The SWOTein webserver provides the list of predicted strengths and weaknesses and a protein structure visualization tool that facilitates the interpretation of the predictions. It is freely available for academic use at http://babylone.ulb.ac.be/SWOTein/

scholarly journals SWOTein: A structure-based approach to predict stability Strengths and Weaknesses of prOTEINs

2020 ◽  
Author(s):  
Q. Hou ◽  
F. Pucci ◽  
F. Ancien ◽  
J.M. Kwasigroch ◽  
R. Bourgeas ◽  
...  
Keyword(s):  
Free Energy ◽  
Large Scale ◽  
Hydrogen Exchange ◽  
Energy Functions ◽  
Functional Regions ◽  
Apocytochrome B ◽  
Amino Acid Binding ◽  
The Individual ◽  
Structured Proteins ◽  
Exchange Data

AbstractMotivationAlthough structured proteins adopt their lowest free energy conformation in physiological conditions, the individual residues are generally not in their lowest free energy conformation. Residues that are stability weaknesses are often involved in functional regions, whereas stability strengths ensure local structural stability. The detection of strengths and weaknesses provides key information to guide protein engineering experiments aiming to modulate folding and various functional processes.ResultsWe developed the SWOTein predictor which identifies strong and weak residues in proteins on the basis of three types of statistical energy functions describing local interactions along the chain, hydrophobic forces and tertiary interactions. The large-scale comparison of the different types of strengths and weaknesses showed their complementarity and the enhancement of the information they provide. We applied SWOTein to apocytochrome b562 and found good agreement between predicted strengths and weaknesses and native hydrogen exchange data. Its application to an amino acid-binding protein identified the hinge at the basis of the conformational change. SWOTein is both fast and accurate and can be applied at small and large scale to analyze and modulate folding and molecular recognition processes.AvailabilityThe SWOTein webserver provides the list of predicted strengths and weaknesses and a protein structure visualization tool that facilitates the interpretation of the predictions. It is freely available for academic use at http://babylone.ulb.ac.be/SWOTein.

scholarly journals Integrin extension enables ultrasensitive regulation by cytoskeletal force

2017 ◽  
Vol 114 (18) ◽  
pp. 4685-4690 ◽  
Author(s):  
Jing Li ◽  
Timothy A. Springer
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Large Scale ◽  
Tensile Force ◽  
Energy Difference ◽  
Length Scale ◽  
Ligand Complex ◽  
Free Energy Difference ◽  
Cytoskeletal Dynamics ◽  
Integrin Ligand

Integrins undergo large-scale conformational changes upon activation. Signaling events driving integrin activation have previously been discussed conceptually, but not quantitatively. Here, recent measurements of the intrinsic ligand-binding affinity and free energy of each integrin conformational state on the cell surface, together with the length scales of conformational change, are used to quantitatively compare models of activation. We examine whether binding of cytoskeletal adaptors to integrin cytoplasmic domains is sufficient for activation or whether exertion of tensile force by the actin cytoskeleton across the integrin–ligand complex is also required. We find that only the combination of adaptor binding and cytoskeletal force provides ultrasensitive regulation. Moreover, switch-like activation by force depends on the large, >130 Å length-scale change in integrin extension, which is well tailored to match the free-energy difference between the inactive (bent-closed) and active (extended-open) conformations. The length scale and energy cost in integrin extension enable activation by force in the low pN range and appear to be the key specializations that enable cell adhesion through integrins to be coordinated with cytoskeletal dynamics.

scholarly journals Microscopic Characterization of the Chloride Permeation Pathway in the Human Excitatory Amino Acid Transporter 1 (EAAT1)

2021 ◽  
Author(s):  
Shashank Pant ◽  
Qianyi Wu ◽  
Renae M Ryan ◽  
Emad Tajkhorshid
Keyword(s):  
Free Energy ◽  
Amino Acid ◽  
Conformational Changes ◽  
Large Scale ◽  
Excitatory Amino Acid ◽  
Free Energy Calculations ◽  
Amino Acid Transporters ◽  
Coupled Transport ◽  
Energy Calculations ◽  
Transport Cycle

Excitatory amino acid transporters (EAATs) are glutamate transporters that belong to the solute carrier 1A (SLC1A) family. They couple glutamate transport to the co-transport of three sodium (Na+) ions and one proton (H+) and the counter-transport of one potassium (K+) ion. In addition to this coupled transport, binding of substrate and Na+ ions to EAATs activates a thermodynamically uncoupled chloride (Cl-) conductance. Structures of SLC1A family members have revealed that these transporters use a twisting elevator mechanism of transport, where a mobile transport domain carries substrate and coupled ions across the membrane, while a static scaffold domain anchors the transporter in the membrane. We have recently demonstrated that the uncoupled Cl- conductance is activated by the formation of an aqueous pore at the domain interface during the transport cycle in archaeal GltPh. However, a pathway for the uncoupled Cl- conductance has not been reported for the EAATs and it is unclear if such a pathway is conserved. Here, we employ all-atom molecular dynamics (MD) simulations combined with enhanced sampling, free-energy calculations, and experimental mutagenesis to approximate large-scale conformational changes during the transport process and identified a Cl- conducting conformation in human EAAT1. We were able to extensively sample the large-scale structural transitions, allowing us to capture an intermediate conformation formed during the transport cycle with a continuous aqueous pore at the domain interface. The free-energy calculations performed for the conduction of Cl- and Na+ ions through the captured conformation, highlight the presence of two hydrophobic gates which control the selective movement of Cl- through the aqueous pathway. Overall, our findings provide insights into the mechanism by which a human glutamate transporter can support the dual functions of active transport and passive Cl- permeation and confirming the commonality of this mechanism in different members of the SLC1A family.

scholarly journals Parallel Distributed Networks Dissociate Episodic and Social Functions Within the Individual

2019 ◽  
Author(s):  
Lauren M. DiNicola ◽  
Rodrigo M. Braga ◽  
Randy L. Buckner
Keyword(s):  
Large Scale ◽  
Distributed Networks ◽  
Association Cortex ◽  
Multiple Forms ◽  
Social Functions ◽  
Temporoparietal Junction ◽  
Cortical Organization ◽  
Functional Regions ◽  
Parahippocampal Cortex ◽  
The Individual

Association cortex is organized into large-scale distributed networks. One such network, the default network (DN), is linked to diverse forms of internal mentation, opening debate about whether shared anatomy supports multiple forms of cognition. Alternatively, subtle distinctions in cortical organization could remain to be resolved. Using within-individual analysis procedures that preserve idiosyncratic details of cortical anatomy, we probed whether multiple tasks from two domains - Episodic Projection and Theory of Mind (ToM) - rely upon the same or distinct networks. In an initial experiment (n=6, subjects scanned 4 times each), we found evidence that Episodic Projection and ToM tasks activate distinct functional regions distributed throughout cortex, with adjacent regions in parietal, temporal, prefrontal and midline zones. These distinctions were predicted by the hypothesis that the DN comprises two parallel, interdigitated networks. One network, linked to parahippocampal cortex (PHC), is preferentially recruited during Episodic Projection, including both remembering the past and imagining the future. A second juxtaposed network, which includes the temporoparietal junction (TPJ), is differentially engaged during multiple forms of ToM tasks. The TPJ-linked network is interwoven with the PHC-linked network in multiple zones, including the posterior and anterior midline, making clear why it is difficult to fully resolve the two networks in group-averaged or lower-resolution data. We replicated all aspects of this network dissociation in a second, prospectively acquired dataset (n=6). These results refine our understanding of the functional-anatomical organization of association cortex as well as raise questions about how functional specialization might arise in parallel, juxtaposed association networks.

scholarly journals Elongation in translation as a dynamic interaction among the ribosome, tRNA, and elongation factors EF-G and EF-Tu

2009 ◽  
Vol 42 (3) ◽  
pp. 159-200 ◽  
Author(s):  
Xabier Agirrezabala ◽  
Joachim Frank
Keyword(s):  
Conformational Changes ◽  
Messenger Rna ◽  
Large Scale ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Structural Data ◽  
Elongation Factors ◽  
Elongation Cycle ◽  
The Individual ◽  
Protein Elongation

AbstractThe ribosome is a complex macromolecular machine that translates the message encoded in the messenger RNA and synthesizes polypeptides by linking the individual amino acids carried by the cognate transfer RNAs (tRNAs). The protein elongation cycle, during which the tRNAs traverse the ribosome in a coordinated manner along a path of more than 100 Å, is facilitated by large-scale rearrangements of the ribosome. These rearrangements go hand in hand with conformational changes of tRNA as well as elongation factors EF-Tu and EF-G – GTPases that catalyze tRNA delivery and translocation, respectively. This review focuses on the structural data related to the dynamics of the ribosomal machinery, which are the basis, in conjunction with existing biochemical, kinetic, and fluorescence resonance energy transfer data, of our knowledge of the decoding and translocation steps of protein elongation.

Models, Practices and Methods of Reading: Evolution in Time and Space

2009 ◽  
pp. 59-64
Author(s):  
Yulia P. Melentyeva
Keyword(s):  
Large Scale ◽  
Social Groups ◽  
National Program ◽  
Time And Space ◽  
Lack Of Information ◽  
The Individual

In recent years as public in general and specialist have been showing big interest to the matters of reading. According to discussion and launch of the “Support and Development of Reading National Program”, many Russian libraries are organizing the large-scale events like marathons, lecture cycles, bibliographic trainings etc. which should draw attention of different social groups to reading. The individual forms of attraction to reading are used much rare. To author’s mind the main reason of such an issue has to be the lack of information about forms and methods of attraction to reading.

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