Folding Kinetics of a Naturally Occurring Helical Peptide: Implication of the Folding Speed Limit of Helical Proteins

2008 ◽  
Vol 112 (30) ◽  
pp. 9146-9150 ◽  
Author(s):  
Smita Mukherjee ◽  
Pramit Chowdhury ◽  
Michelle R. Bunagan ◽  
Feng Gai
Keyword(s):  
Speed Limit ◽  
Folding Kinetics ◽  
Naturally Occurring ◽  
Helical Peptide ◽  
Helical Proteins ◽  
Kinetics Of

scholarly journals Ultrafast folding kinetics of WW domains reveal how the amino acid sequence determines the speed limit to protein folding

2019 ◽  
Vol 116 (17) ◽  
pp. 8137-8142 ◽  
Author(s):  
Malwina Szczepaniak ◽  
Manuel Iglesias-Bexiga ◽  
Michele Cerminara ◽  
Mourad Sadqi ◽  
Celia Sanchez de Medina ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Essential Element ◽  
Nanosecond Laser ◽  
Speed Limit ◽  
Free Energy Barrier ◽  
Folding Kinetics ◽  
Folding Rate ◽  
Ww Domains ◽  
Kinetics Of

Protein (un)folding rates depend on the free-energy barrier separating the native and unfolded states and a prefactor term, which sets the timescale for crossing such barrier or folding speed limit. Because extricating these two factors is usually unfeasible, it has been common to assume a constant prefactor and assign all rate variability to the barrier. However, theory and simulations postulate a protein-specific prefactor that contains key mechanistic information. Here, we exploit the special properties of fast-folding proteins to experimentally resolve the folding rate prefactor and investigate how much it varies among structural homologs. We measure the ultrafast (un)folding kinetics of five natural WW domains using nanosecond laser-induced temperature jumps. All five WW domains fold in microseconds, but with a 10-fold difference between fastest and slowest. Interestingly, they all produce biphasic kinetics in which the slower phase corresponds to reequilibration over the small barrier (<3RT) and the faster phase to the downhill relaxation of the minor population residing at the barrier top [transition state ensemble (TSE)]. The fast rate recapitulates the 10-fold range, demonstrating that the folding speed limit of even the simplest all-β fold strongly depends on the amino acid sequence. Given this fold’s simplicity, the most plausible source for such prefactor differences is the presence of nonnative interactions that stabilize the TSE but need to break up before folding resumes. Our results confirm long-standing theoretical predictions and bring into focus the rate prefactor as an essential element for understanding the mechanisms of folding.

scholarly journals A comparison of the folding kinetics of a small, artificially selected DNA aptamer with those of equivalently simple naturally occurring proteins

2013 ◽  
Vol 23 (1) ◽  
pp. 56-66 ◽  
Author(s):  
Camille Lawrence ◽  
Alexis Vallée-Bélisle ◽  
Shawn H. Pfeil ◽  
Derek de Mornay ◽  
Everett A. Lipman ◽  
...  
Keyword(s):  
Dna Aptamer ◽  
Folding Kinetics ◽  
Naturally Occurring ◽  
Kinetics Of

scholarly journals Deciphering the folding kinetics of transmembrane helical proteins

2000 ◽  
Vol 97 (26) ◽  
pp. 14229-14234 ◽  
Author(s):  
E. Orlandini ◽  
F. Seno ◽  
J. R. Banavar ◽  
A. Laio ◽  
A. Maritan
Keyword(s):  
Folding Kinetics ◽  
Helical Proteins ◽  
Kinetics Of

scholarly journals Interpreting the folding kinetics of helical proteins

Nature ◽  
10.1038/43937 ◽  
1999 ◽  
Vol 401 (6751) ◽  
pp. 400-403 ◽  
Author(s):  
Yaoqi Zhou ◽  
Martin Karplus
Keyword(s):  
Folding Kinetics ◽  
Helical Proteins ◽  
Kinetics Of

scholarly journals Size and topology modulate the effects of frustration in protein folding

2018 ◽  
Vol 115 (37) ◽  
pp. 9234-9239 ◽  
Author(s):  
Alex Kluber ◽  
Timothy A. Burt ◽  
Cecilia Clementi
Keyword(s):  
Protein Folding ◽  
Folding Kinetics ◽  
Native Structure ◽  
And Topology ◽  
Folding Dynamics ◽  
Helical Proteins ◽  
Experimental Findings ◽  
State Size ◽  
Kinetics Of ◽  
Β Sheet

The presence of conflicting interactions, or frustration, determines how fast biomolecules can explore their configurational landscapes. Recent experiments have provided cases of systems with slow reconfiguration dynamics, perhaps arising from frustration. While it is well known that protein folding speed and mechanism are strongly affected by the protein native structure, it is still unknown how the response to frustration is modulated by the protein topology. We explore the effects of nonnative interactions in the reconfigurational and folding dynamics of proteins with different sizes and topologies. We find that structural correlations related to the folded state size and topology play an important role in determining the folding kinetics of proteins that otherwise have the same amount of nonnative interactions. In particular, we find that the reconfiguration dynamics of α-helical proteins are more susceptible to frustration than β-sheet proteins of the same size. Our results may explain recent experimental findings and suggest that attempts to measure the degree of frustration due to nonnative interactions might be more successful with α-helical proteins.

scholarly journals Simulation of Folding Kinetics for Aligned RNAs

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 347
Author(s):  
Jiabin Huang ◽  
Björn Voß
Keyword(s):  
Evolutionary Conservation ◽  
Folding Kinetics ◽  
New Approach ◽  
Computational Approaches ◽  
Reasonable Time ◽  
Valuable Method ◽  
Kinetics Of ◽  
Insight Into ◽  
Folding Space ◽  
Standing Problem

Studying the folding kinetics of an RNA can provide insight into its function and is thus a valuable method for RNA analyses. Computational approaches to the simulation of folding kinetics suffer from the exponentially large folding space that needs to be evaluated. Here, we present a new approach that combines structure abstraction with evolutionary conservation to restrict the analysis to common parts of folding spaces of related RNAs. The resulting algorithm can recapitulate the folding kinetics known for single RNAs and is able to analyse even long RNAs in reasonable time. Our program RNAliHiKinetics is the first algorithm for the simulation of consensus folding kinetics and addresses a long-standing problem in a new and unique way.

scholarly journals Desensitization Contributes to the Synaptic Response of Gain-of-Function Mutants of the Muscle Nicotinic Receptor

2006 ◽  
Vol 128 (5) ◽  
pp. 615-627 ◽  
Author(s):  
Sergio Elenes ◽  
Ying Ni ◽  
Gisela D. Cymes ◽  
Claudio Grosman
Keyword(s):  
Nicotinic Receptor ◽  
Dissociation Rate ◽  
Gain Of Function ◽  
Naturally Occurring ◽  
Channel Opening ◽  
Speed Up ◽  
High Concentrations ◽  
Dissociation Rate Constants ◽  
Kinetics Of ◽  
Peak Value

Although the muscle nicotinic receptor (AChR) desensitizes almost completely in the steady presence of high concentrations of acetylcholine (ACh), it is well established that AChRs do not accumulate in desensitized states under normal physiological conditions of neurotransmitter release and clearance. Quantitative considerations in the framework of plausible kinetic schemes, however, lead us to predict that mutations that speed up channel opening, slow down channel closure, and/or slow down the dissociation of neurotransmitter (i.e., gain-of-function mutations) increase the extent to which AChRs desensitize upon ACh removal. In this paper, we confirm this prediction by applying high-frequency trains of brief (∼1 ms) ACh pulses to outside-out membrane patches expressing either lab-engineered or naturally occurring (disease-causing) gain-of-function mutants. Entry into desensitization was evident in our experiments as a frequency-dependent depression in the peak value of succesive macroscopic current responses, in a manner that is remarkably consistent with the theoretical expectation. We conclude that the comparatively small depression of the macroscopic currents observed upon repetitive stimulation of the wild-type AChR is due, not to desensitization being exceedingly slow but, rather, to the particular balance between gating, entry into desensitization, and ACh dissociation rate constants. Disruption of this fine balance by, for example, mutations can lead to enhanced desensitization even if the kinetics of entry into, and recovery from, desensitization themselves are not affected. It follows that accounting for the (usually overlooked) desensitization phenomenon is essential for the correct interpretation of mutagenesis-driven structure–function relationships and for the understanding of pathological synaptic transmission at the vertebrate neuromuscular junction.

scholarly journals Modulation of Folding Kinetics of Repeat Proteins: Interplay between Intra- and Interdomain Interactions

2012 ◽  
Vol 103 (7) ◽  
pp. 1555-1565 ◽  
Author(s):  
Tzachi Hagai ◽  
Ariel Azia ◽  
Emmanuel Trizac ◽  
Yaakov Levy
Keyword(s):  
Folding Kinetics ◽  
Repeat Proteins ◽  
Interdomain Interactions ◽  
Kinetics Of

Absorption of beta-casomorphins from autoperfused lamb and piglet small intestine

1990 ◽  
Vol 259 (3) ◽  
pp. G443-G452 ◽  
Author(s):  
L. C. Read ◽  
A. P. Lord ◽  
V. Brantl ◽  
G. Koch
Keyword(s):  
Small Intestine ◽  
Intestinal Lumen ◽  
Physiological Conditions ◽  
Naturally Occurring ◽  
Gut Epithelium ◽  
Measured Absorption ◽  
Beta Casein ◽  
Kinetics Of

beta-Casomorphins (beta-CMs) derived from milk beta-casein may exert various opiate activities in milk-fed infants. To assess the physiological significance of beta-CMs as a source of circulating opioids in infants, we measured absorption rates of several beta-CMs under near-physiological conditions using in situ autoperfused lamb intestine. The naturally occurring beta-CMs, beta-CM-7 and beta-CM-4-amide, were absorbed readily into blood with no transfer into lymph. Uptake peaked within several minutes of the luminal infusion of peptide but then declined sharply and stopped within a further 10-15 min. The recovery in blood, intestinal contents, and tissue at the end of the 30-min experiment was less than 1% of the infused dose. The low recovery was due to rapid proteolysis based on in vitro studies that demonstrated half-lives of less than 5 min in lamb blood, luminal contents, and lymph. The synthetic dipeptidyl peptidase IV-resistant analogue beta-[D-Ala2]CM- 4-amide was stable during incubation in blood, lymph, or luminal contents and was absorbed into blood at rates that were maximal within several minutes and remained steady for the 30-min period. We conclude that although natural beta-CMs are transferred across the lamb small intestine, rapid degradation within the intestinal lumen, gut epithelium, and blood would prevent entry into the circulation under normal conditions. Val-beta-CM-7, a putative stable precursor, had similar stability and kinetics of absorption to beta-CM-7, results that exclude Val-beta-CM-7 as a stable precursor for delivery of beta-CMs to the circulation. Essentially identical results to those in lambs were obtained in 7-day-old piglets.

Stability and Folding Kinetics of Structurally Characterized Cytochromec-b562†,‡

Biochemistry ◽  
2006 ◽  
Vol 45 (35) ◽  
pp. 10504-10511 ◽  
Author(s):  
Jasmin Faraone-Mennella ◽  
F. Akif Tezcan ◽  
Harry B. Gray ◽  
Jay R. Winkler
Keyword(s):  
Folding Kinetics ◽  
Kinetics Of
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