Divergent folding pathways of two homologous proteins, BPTI and tick anticoagulant peptide: Compartmentalization of folding intermediates and identification of kinetic traps

2005 ◽  
Vol 437 (1) ◽  
pp. 85-95 ◽  
Author(s):  
Jui-Yoa Chang ◽  
Li Li
Keyword(s):  
Homologous Proteins ◽  
Folding Intermediates ◽  
Folding Pathways ◽  
Kinetic Traps ◽  
Tick Anticoagulant Peptide

scholarly journals Comparison of successive transition states for folding reveals alternative early folding pathways of two homologous proteins

2008 ◽  
Vol 105 (49) ◽  
pp. 19241-19246 ◽  
Author(s):  
N. Calosci ◽  
C. N. Chi ◽  
B. Richter ◽  
C. Camilloni ◽  
A. Engstrom ◽  
...  
Keyword(s):  
Transition States ◽  
Homologous Proteins ◽  
Folding Pathways

A COMPARATIVE ANALYSIS OF FOLDING PATHWAYS OF THERMOPHILIC AND MESOPHILIC PROTEINS BY MONTE CARLO SIMULATIONS

2010 ◽  
Vol 08 (03) ◽  
pp. 395-411 ◽  
Author(s):  
ANNA V. GLYAKINA ◽  
OXANA V. GALZITSKAYA
Keyword(s):  
Monte Carlo ◽  
Free Energy ◽  
Monte Carlo Simulations ◽  
Energy Barrier ◽  
Free Energy Barrier ◽  
Homologous Proteins ◽  
Structural Class ◽  
Class D ◽  
Folding Pathways ◽  
First Occurrence

In this work we have studied the folding pathways for four pairs of homologous proteins from thermophilic and mesophilic organisms from two different structural classes (class a, all-α proteins and class d, α + β proteins) using Monte Carlo simulations. We have obtained 50 trajectories for each protein and followed the free-energy profile and the order of folding of secondary structure elements between the last occurrence of the completely unfolded state and the first occurrence of the completely folded state. It turns out that the period of successful crossing of the free-energy barrier between unfolded and folded states for 40–45 trajectories (80–90%) makes 10% of the total folding time for four proteins (1tzvA, 1eyvA, 351c, and 1t4aA) and only 0.1% for two proteins (1dd3, 1ctf). This observation can be explained by a higher free-energy barrier for these proteins (1dd3, 1ctf) in comparison with other studied proteins. We have observed that folding pathways of thermophilic and mesophilic proteins may be the same, partly the same, and different. And similarity or difference between the folding pathways of thermophilic and mesophilic proteins does not depend on the structural class to which these proteins belong. Folding pathways for proteins from both classes correlate with the calculated folding nuclei for these proteins.

scholarly journals Computationally Reconstructing Cotranscriptional RNA Folding Pathways from Experimental Data Reveals Rearrangement of Non-Native Folding Intermediates

2018 ◽  
Author(s):  
Angela M Yu ◽  
Paul M. Gasper ◽  
Eric J. Strobel ◽  
Kyle E. Watters ◽  
Alan A. Chen ◽  
...  
Keyword(s):  
Rna Folding ◽  
Signal Recognition Particle ◽  
Point Mutations ◽  
Structural Rearrangement ◽  
Folding Pathway ◽  
List Type ◽  
Folding Intermediates ◽  
Folding Pathways ◽  
Dynamics Simulations ◽  
Srp Rna

SummaryThe series of RNA folding events that occur during transcription, or a cotranscriptional folding pathway, can critically influence the functional roles of RNA in the cell. Here we present a method, Reconstructing RNA Dynamics from Data (R2D2), to uncover details of cotranscriptional folding pathways by predicting RNA secondary and tertiary structures from cotranscriptional SHAPE-Seq data. We applied R2D2 to the folding of the Escherichia coli Signal Recognition Particle (SRP) RNA sequence and show that this sequence undergoes folding through non-native intermediate structures that require significant structural rearrangement before reaching the functional native structure. Secondary structure folding pathway predictions and all-atom molecular dynamics simulations of folding intermediates suggest that this rearrangement can proceed through a toehold mediated strand displacement mechanism, which can be disrupted and rescued with point mutations. These results demonstrate that even RNAs with simple functional folds can undergo complex folding processes during synthesis, and that small variations in their sequence can drastically affect their cotranscriptional folding pathways.Highlights- Computational methods predict RNA structures from cotranscriptional SHAPE-Seq data- The E. coli SRP RNA folds into non-native structural intermediates cotranscriptionally- These structures rearrange dynamically to form an extended functional fold- Point mutations can disrupt and rescue cotranscriptional RNA folding pathways

Different Folding Pathways Taken by Highly Homologous Proteins, Goat α-Lactalbumin and Canine Milk Lysozyme

2010 ◽  
Vol 396 (5) ◽  
pp. 1361-1378 ◽  
Author(s):  
Takashi Nakamura ◽  
Koki Makabe ◽  
Katsuaki Tomoyori ◽  
Kosuke Maki ◽  
Atsushi Mukaiyama ◽  
...  
Keyword(s):  
Homologous Proteins ◽  
Folding Pathways

scholarly journals Parallel G-triplexes and G-hairpins as potential transitory ensembles in the folding of parallel-stranded DNA G-Quadruplexes

2019 ◽  
Vol 47 (14) ◽  
pp. 7276-7293 ◽  
Author(s):  
Petr Stadlbauer ◽  
Petra Kührová ◽  
Lukáš Vicherek ◽  
Pavel Banáš ◽  
Michal Otyepka ◽  
...  
Keyword(s):  
Single Molecule ◽  
Local Equilibrium ◽  
Enhanced Sampling ◽  
Loop Formation ◽  
Folding Intermediates ◽  
G4 Dna ◽  
Folding Pathways ◽  
Dynamics Simulations ◽  
Genomic Regions

Abstract Guanine quadruplexes (G4s) are non-canonical nucleic acids structures common in important genomic regions. Parallel-stranded G4 folds are the most abundant, but their folding mechanism is not fully understood. Recent research highlighted that G4 DNA molecules fold via kinetic partitioning mechanism dominated by competition amongst diverse long-living G4 folds. The role of other intermediate species such as parallel G-triplexes and G-hairpins in the folding process has been a matter of debate. Here, we use standard and enhanced-sampling molecular dynamics simulations (total length of ∼0.9 ms) to study these potential folding intermediates. We suggest that parallel G-triplex per se is rather an unstable species that is in local equilibrium with a broad ensemble of triplex-like structures. The equilibrium is shifted to well-structured G-triplex by stacked aromatic ligand and to a lesser extent by flanking duplexes or nucleotides. Next, we study propeller loop formation in GGGAGGGAGGG, GGGAGGG and GGGTTAGGG sequences. We identify multiple folding pathways from different unfolded and misfolded structures leading towards an ensemble of intermediates called cross-like structures (cross-hairpins), thus providing atomistic level of description of the single-molecule folding events. In summary, the parallel G-triplex is a possible, but not mandatory short-living (transitory) intermediate in the folding of parallel-stranded G4.

scholarly journals Protein folding and misfolding: mechanism and principles

2007 ◽  
Vol 40 (4) ◽  
pp. 1-41 ◽  
Author(s):  
S. Walter Englander ◽  
Leland Mayne ◽  
Mallela M. G. Krishna
Keyword(s):  
Protein Folding ◽  
Hydrogen Exchange ◽  
Building Blocks ◽  
Native Protein ◽  
Native State ◽  
Stabilization Mechanism ◽  
Structural Units ◽  
Folding Intermediates ◽  
Folding Pathways ◽  
Protein Folding Pathways

AbstractTwo fundamentally different views of how proteins fold are now being debated. Do proteins fold through multiple unpredictable routes directed only by the energetically downhill nature of the folding landscape or do they fold through specific intermediates in a defined pathway that systematically puts predetermined pieces of the target native protein into place? It has now become possible to determine the structure of protein folding intermediates, evaluate their equilibrium and kinetic parameters, and establish their pathway relationships. Results obtained for many proteins have serendipitously revealed a new dimension of protein structure. Cooperative structural units of the native protein, called foldons, unfold and refold repeatedly even under native conditions. Much evidence obtained by hydrogen exchange and other methods now indicates that cooperative foldon units and not individual amino acids account for the unit steps in protein folding pathways. The formation of foldons and their ordered pathway assembly systematically puts native-like foldon building blocks into place, guided by a sequential stabilization mechanism in which prior native-like structure templates the formation of incoming foldons with complementary structure. Thus the same propensities and interactions that specify the final native state, encoded in the amino-acid sequence of every protein, determine the pathway for getting there. Experimental observations that have been interpreted differently, in terms of multiple independent pathways, appear to be due to chance misfolding errors that cause different population fractions to block at different pathway points, populate different pathway intermediates, and fold at different rates. This paper summarizes the experimental basis for these three determining principles and their consequences. Cooperative native-like foldon units and the sequential stabilization process together generate predetermined stepwise pathways. Optional misfolding errors are responsible for 3-state and heterogeneous kinetic folding.

scholarly journals Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins

2018 ◽  
Vol 9 (13) ◽  
pp. 3290-3298 ◽  
Author(s):  
Gaetano Malgieri ◽  
Gianluca D'Abrosca ◽  
Luciano Pirone ◽  
Angelo Toto ◽  
Maddalena Palmieri ◽  
...  
Keyword(s):  
Amyloid Fibril ◽  
Fibril Formation ◽  
Homologous Proteins ◽  
Amyloid Fibril Formation ◽  
Molecular Determinants ◽  
Folding Pathways

Understanding the molecular determinants of fibrillogenesis by studying the aggregation propensities of high homologous proteins with different folding pathways.

Inhibition of Thrombin Generation in Plasma by Inhibitors of Factor Xa

1997 ◽  
Vol 78 (04) ◽  
pp. 1215-1220 ◽  
Author(s):  
D Prasa ◽  
L Svendsen ◽  
J Stürzebecher
Keyword(s):  
Thrombin Generation ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Thrombin Generation Assay ◽  
Ic50 Values ◽  
Fxa Inhibitor ◽  
20 Nm ◽  
Tick Anticoagulant Peptide ◽  
Inhibition Of Thrombin

SummaryA series of inhibitors of factor Xa (FXa) were investigated using the thrombin generation assay to evaluate the potency and specificity needed to efficiently block thrombin generation in activated human plasma. By inhibiting FXa the generation of thrombin in plasma is delayed and decreased. Inhibitor concentrations which cause 50 percent inhibition of thrombin generation (IC50) correlate in principle with the Ki values for inhibition of free FXa. Recombinant tick anticoagulant peptide (r-TAP) is able to inhibit thrombin generation with considerably low IC50 values of 49 nM and 37 nM for extrinsic and intrinsic activation, respectively. However, the potent synthetic, low molecular weight inhibitors of FXa (Ki values of about 20 nM) are less effective in inhibiting the generation of thrombin with IC50 values at micromolar concentrations.The overall effect of inhibitors of FXa in the thrombin generation assay was compared to that of thrombin inhibitors. On the basis of similar Ki values for the inhibition of the respective enzyme, synthetic FXa inhibitors are less effective than thrombin inhibitors. In contrast, the highly potent FXa inhibitor r-TAP causes a stronger reduction of the thrombin activity in plasma than the most potent thrombin inhibitor hirudin.

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