Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Stabilization of a protein conferred by an increase in folded state entropy.

ABSTRACT: Entropic stabilization of native protein structures typically relies on strategies that serve to decrease the entropy of the unfolded state. Here we report, using a combination of experimental and computational approaches, on enhanced thermodynamic stability conferred by an increase in the configurational entropy of the folded state. The enhanced stability is observed upon modifications of a loop region in the enzyme acylphosphatase and is achieved despite significant enthalpy losses. The modifications that lead to increased stability, as well as those that result in destabilization, however, strongly compromise enzymatic activity, rationalizing the preservation of the native loop structure even though it does not provide the protein with maximal stability or kinetic foldability.

SUBMITTER: Dagan S

PROVIDER: S-EPMC3696814 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Stabilization of a protein conferred by an increase in folded state entropy.

Dagan Shlomi S Hagai Tzachi T Gavrilov Yulian Y Kapon Ruti R Levy Yaakov Y Reich Ziv Z

Proceedings of the National Academy of Sciences of the United States of America 20130610 26

Entropic stabilization of native protein structures typically relies on strategies that serve to decrease the entropy of the unfolded state. Here we report, using a combination of experimental and computational approaches, on enhanced thermodynamic stability conferred by an increase in the configurational entropy of the folded state. The enhanced stability is observed upon modifications of a loop region in the enzyme acylphosphatase and is achieved despite significant enthalpy losses. The modifi ...[more]

PMID: 23754389

Similar Datasets

Bioinformatic method for protein thermal stabilization by structural entropy optimization.

Project description:Engineering proteins for higher thermal stability is an important and difficult challenge. We describe a bioinformatic method incorporating sequence alignments to redesign proteins to be more stable through optimization of local structural entropy. Using this method, improved configurational entropy (ICE), we were able to design more stable variants of a mesophilic adenylate kinase with only the sequence information of one psychrophilic homologue. The redesigned proteins display considerable increases in their thermal stabilities while still retaining catalytic activity. ICE does not require a three-dimensional structure or a large number of homologous sequences, indicating a broad applicability of this method. Our results also highlight the importance of entropy in the stability of protein structures.

| S-EPMC2474475 | biostudies-literature

Thermodynamic stabilization of the folded domain of prion protein inhibits prion infection in vivo.

Project description:Prion diseases, or transmissible spongiform encephalopathies (TSEs), are associated with the conformational conversion of the cellular prion protein, PrP(C), into a protease-resistant form, PrP(Sc). Here, we show that mutation-induced thermodynamic stabilization of the folded, ?-helical domain of PrP(C) has a dramatic inhibitory effect on the conformational conversion of prion protein in vitro, as well as on the propagation of TSE disease in vivo. Transgenic mice expressing a human prion protein variant with increased thermodynamic stability were found to be much more resistant to infection with the TSE agent than those expressing wild-type human prion protein, in both the primary passage and three subsequent subpassages. These findings not only provide a line of evidence in support of the protein-only model of TSEs but also yield insight into the molecular nature of the PrP(C)?PrP(Sc) conformational transition, and they suggest an approach to the treatment of prion diseases.

| S-EPMC3766954 | biostudies-literature

Phase stabilization by electronic entropy in plutonium.

Project description:Plutonium metal undergoes an anomalously large 25% collapse in volume from its largest volume δ phase (δ-Pu) to its low temperature α phase, yet the underlying thermodynamic mechanism has largely remained a mystery. Here we use magnetostriction measurements to isolate a previously hidden yet substantial electronic contribution to the entropy of δ-Pu, which we show to be crucial for the stabilization of this phase. The entropy originates from two competing instabilities of the 5f-electron shell, which we show to drive the volume of Pu in opposing directions, depending on the temperature and volume. Using calorimetry measurements, we establish a robust thermodynamic connection between the two excitation energies, the atomic volume, and the previously reported excess entropy of δ-Pu at elevated temperatures.

| S-EPMC6639308 | biostudies-literature

AHSP (?-haemoglobin-stabilizing protein) stabilizes apo-?-haemoglobin in a partially folded state.

Project description:To produce functional Hb (haemoglobin), nascent ?-globin (?o) and ?-globin (?o) chains must each bind a single haem molecule (to form ?h and ?h) and interact together to form heterodimers. The precise sequence of binding events is unknown, and it has been suggested that additional factors might enhance the efficiency of Hb folding. AHSP (?-haemoglobin-stabilizing protein) has been shown previously to bind ?h and regulate redox activity of the haem iron. In the present study, we used a combination of classical and dynamic light scattering and NMR spectroscopy to demonstrate that AHSP forms a heterodimeric complex with ?o that inhibits ?o aggregation and promotes ?o folding in the absence of haem. These findings indicate that AHSP may function as an ?o-specific chaperone, and suggest an important role for ?o in guiding Hb assembly by stabilizing ?o and inhibiting off-pathway self-association of ?h.

| S-EPMC4384432 | biostudies-literature

Biological function in a non-native partially folded state of a protein.

Project description:As structural flexibility is known to be required for enzyme catalysis and pattern recognition and a significant fraction of eukaryotic proteins appear to be unfolded or contain unstructured regions, biological activity of conformational states distinct from fully folded structures could be more common than previously thought. By applying a procedure that allows the recovery of enzymatic activity to be monitored in real time, we show that a non-native state populated transiently during folding of the acylphosphatase from Sulfolobus solfataricus is enzymatically active. The structural characterization of this partially folded state reveals that enzymatic activity is possible even if the catalytic site is structurally heterogeneous, whereas the remainder of the structure acts as a scaffold. These results extend the spectrum of biological functions carried out in the absence of a folded state to include enzyme catalysis.

| S-EPMC2396399 | biostudies-literature

Entropy from state probabilities: hydration entropy of cations.

Project description:Entropy is an important energetic quantity determining the progression of chemical processes. We propose a new approach to obtain hydration entropy directly from probability density functions in state space. We demonstrate the validity of our approach for a series of cations in aqueous solution. Extensive validation of simulation results was performed. Our approach does not make prior assumptions about the shape of the potential energy landscape and is capable of calculating accurate hydration entropy values. Sampling times in the low nanosecond range are sufficient for the investigated ionic systems. Although the presented strategy is at the moment limited to systems for which a scalar order parameter can be derived, this is not a principal limitation of the method. The strategy presented is applicable to any chemical system where sufficient sampling of conformational space is accessible, for example, by computer simulations.

| S-EPMC3668459 | biostudies-literature

Selective stabilization of natively folded RNA structure by DNA constraints.

Project description:Learning how native RNA conformations can be stabilized relative to unfolded states is an important objective, for both understanding natural RNAs and improving the design of artificial functional RNAs. Here we show that covalently attached double-stranded DNA constraints (ca. 14 base pairs in length) can significantly stabilize the native conformation of an RNA molecule. Using the P4-P6 domain of the Tetrahymena group I intron as the test system, we identified pairs of RNA sites where attaching a DNA duplex is predicted to be structurally compatible with only the folded state of the RNA. The DNA-constrained RNAs were synthesized and shown by nondenaturing polyacrylamide gel electrophoresis (native PAGE) to have substantial decreases in their Mg2+ midpoints ([Mg2+]1/2 values). These changes are equivalent to free energy stabilizations as large as DeltaDeltaGdegrees = -2.5 kcal/mol, which is approximately 14% of the total tertiary folding energy. For comparison, the sole modification of P4-P6 previously reported to stabilize this RNA is a single-nucleotide deletion (DeltaC209) that provides only 1.1 kcal/mol of stabilization. Our findings indicate that nature has not completely optimized P4-P6 RNA folding. Furthermore, the DNA constraints are designed not to interact directly and extensively with the RNA, but rather more indirectly to modulate the relative stabilities of folded and unfolded RNA states. The successful implementation of this strategy to further stabilize a natively folded RNA conformation suggests an important element of modularity in stabilization of RNA structure, with implications for how nature might use other molecules such as proteins to stabilize specific RNA conformations.

| S-EPMC2628330 | biostudies-literature

Configurational Entropy of Folded Proteins and Its Importance for Intrinsically Disordered Proteins.

Project description:Many pairwise additive force fields are in active use for intrinsically disordered proteins (IDPs) and regions (IDRs), some of which modify energetic terms to improve the description of IDPs/IDRs but are largely in disagreement with solution experiments for the disordered states. This work considers a new direction-the connection to configurational entropy-and how it might change the nature of our understanding of protein force field development to equally well encompass globular proteins, IDRs/IDPs, and disorder-to-order transitions. We have evaluated representative pairwise and many-body protein and water force fields against experimental data on representative IDPs and IDRs, a peptide that undergoes a disorder-to-order transition, for seven globular proteins ranging in size from 130 to 266 amino acids. We find that force fields with the largest statistical fluctuations consistent with the radius of gyration and universal Lindemann values for folded states simultaneously better describe IDPs and IDRs and disorder-to-order transitions. Hence, the crux of what a force field should exhibit to well describe IDRs/IDPs is not just the balance between protein and water energetics but the balance between energetic effects and configurational entropy of folded states of globular proteins.

| S-EPMC8037987 | biostudies-literature

Entropic stabilization of folded RNA in crowded solutions measured by SAXS.

Project description:Non-coding RNAs must fold into specific structures that are stabilized by metal ions and other co-solutes in the cell's interior. Large crowder molecules such as PEG stabilize a bacterial group I ribozyme so that the RNA folds in low Mg2+ concentrations typical of the cell's interior. To understand the thermodynamic origins of stabilization by crowder molecules, small angle X-ray scattering was used to measure the folding and helix assembly of a bacterial group I ribozyme at different temperatures and in different MgCl2 and polyethylene glycol (PEG) concentrations. The resulting phase diagrams show that perturbations to folding by each variable do not overlap. A favorable enthalpy change drives the formation of compact, native-like structures, but requires Mg2+ ions at all temperatures studied (5-55°C). PEG reduces the entropic cost of helix assembly and increases correlations between RNA segments at all temperatures. The phase diagrams also revealed a semi-compact intermediate between the unfolded and folded ensemble that is locally more flexible than the unfolded state, as judged by SHAPE modification. These results suggest that environmental variables such as temperature and solute density will favor different types of RNA structures.

| S-EPMC5100557 | biostudies-literature

Entropic stabilization of the folded states of RNA due to macromolecular crowding.

Project description:We review the effects of macromolecular crowding on the folding of RNA by considering the simplest scenario when excluded volume interactions between crowding particles and RNA dominate. Using human telomerase enzyme as an example, we discuss how crowding can alter the equilibrium between pseudoknot and hairpin states of the same RNA molecule-a key aspect of crowder-RNA interactions. We summarize data showing that the crowding effect is significant only if the size of the spherical crowding particle is smaller than the radius of gyration of the RNA in the absence of crowding particles. The implication for function of the wild type and mutants of human telomerase is outlined by using a relationship between enzyme activity and its conformational equilibrium. In addition, we discuss the interplay between macromolecular crowding and ionic strength of the RNA buffer. Finally, we briefly review recent experiments which illustrate the connection between excluded volume due to macromolecular crowding and the thermodynamics of RNA folding.

| S-EPMC5425724 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data