Free Energy Surfaces for the α(1 → 4)-Glycosidic Linkage:  Implications for Polysaccharide Solution Structure and Dynamics

2005 ◽  
Vol 109 (15) ◽  
pp. 7468-7474 ◽  
Author(s):  
Michelle M. Kuttel ◽  
Kevin J. Naidoo
Keyword(s):  
Free Energy ◽  
Solution Structure ◽  
Glycosidic Linkage ◽  
Structure And Dynamics ◽  
Energy Surfaces

scholarly journals Free Energy Landscape and Rate Estimation of the Aromatic Ring Flips in Basic Pancreatic Trypsin Inhibitor Using Metadynamics

2021 ◽  
Author(s):  
Pär Söderhjelm ◽  
Mandar Kulkarni
Keyword(s):  
Free Energy ◽  
Trypsin Inhibitor ◽  
Side Chain ◽  
Side Chains ◽  
Aromatic Residues ◽  
Basic Pancreatic Trypsin Inhibitor ◽  
Pancreatic Trypsin Inhibitor ◽  
Energy Surfaces ◽  
Aromatic Side Chains

Aromatic side-chains (phenylalanine and tyrosine) of a protein flip by 180° around the Cβ-Cγ axis (χ2 dihedral of side-chain) producing two symmetry-equivalent states. The ring-flip dynamics act as an NMR probe to understand local conformational fluctuations. Ring-flips are categorized as slow (ms onwards) or fast (ns to near ms) based on timescales accessible to NMR experiments. In this study, we investigated the ability of the infrequent metadynamics approach to discriminate between slow and fast ring-flips for eight individual aromatic side-chains (F4, Y10, Y21, F22, Y23, F33, Y35, F45) of basic pancreatic trypsin inhibitor (BPTI). Well-tempered metadynamics simulations were performed to observe ring-flipping free energy surfaces for all eight aromatic residues. The results indicate that χ2 as a standalone collective variable (CV) is not sufficient to classify fast and slow ring-flips. Most of the residues needed χ1 (N−Cχα) as a complementary CV, indicating the importance of librational motions in ring-flips. Multiple pathways and mechanisms were observed for residues F4, Y10, and F22. Recrossing events are observed for residues F22 and F33, indicating a possible role of friction effects in the ring-flipping. The results demonstrate the successful application of the metadynamics based approach to estimate ring-flip rates of aromatic residues in BPTI and identify certain limitations of the approach.

Calculating Ring Pucker Free Energy Surfaces From Reaction Coordinate Forces

2009 ◽  
Author(s):  
Christopher B. Barnett ◽  
Kevin J. Naidoo ◽  
Dong-Qing Wei ◽  
Xi-Jun Wang
Keyword(s):  
Free Energy ◽  
Reaction Coordinate ◽  
Energy Surfaces ◽  
Ring Pucker

Solution structure and dynamics of glia maturation factor from Caenorhabditis elegans

2018 ◽  
Vol 1866 (10) ◽  
pp. 1008-1020 ◽  
Author(s):  
Diva Maheshwari ◽  
Vaibhav Kumar Shukla ◽  
Anupam Jain ◽  
Sarita Tripathi ◽  
Dinesh Kumar ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Solution Structure ◽  
Glia Maturation Factor ◽  
Structure And Dynamics ◽  
Maturation Factor

The A39G FF domain folds on a volcano-shaped free energy surface via separate pathways

2021 ◽  
Vol 118 (46) ◽  
pp. e2115113118
Author(s):  
Ved P. Tiwari ◽  
Yuki Toyama ◽  
Debajyoti De ◽  
Lewis E. Kay ◽  
Pramodh Vallurupalli
Keyword(s):  
Free Energy ◽  
Chemical Exchange ◽  
Exchange Process ◽  
Conformational Dynamics ◽  
Chemical Exchange Saturation Transfer ◽  
Folding Kinetics ◽  
Free Energy Surface ◽  
Wide Range ◽  
Order Of Magnitude ◽  
Energy Surfaces

Conformational dynamics play critical roles in protein folding, misfolding, function, misfunction, and aggregation. While detecting and studying the different conformational states populated by protein molecules on their free energy surfaces (FESs) remain a challenge, NMR spectroscopy has emerged as an invaluable experimental tool to explore the FES of a protein, as conformational dynamics can be probed at atomic resolution over a wide range of timescales. Here, we use chemical exchange saturation transfer (CEST) to detect “invisible” minor states on the energy landscape of the A39G mutant FF domain that exhibited “two-state” folding kinetics in traditional experiments. Although CEST has mostly been limited to studies of processes with rates between ∼5 to 300 s−1 involving sparse states with populations as low as ∼1%, we show that the line broadening that is often associated with minor state dips in CEST profiles can be exploited to inform on additional conformers, with lifetimes an order of magnitude shorter and populations close to 10-fold smaller than what typically is characterized. Our analysis of CEST profiles that exploits the minor state linewidths of the 71-residue A39G FF domain establishes a folding mechanism that can be described in terms of a four-state exchange process between interconverting states spanning over two orders of magnitude in timescale from ∼100 to ∼15,000 μs. A similar folding scheme is established for the wild-type domain as well. The study shows that the folding of this small domain proceeds through a pair of sparse, partially structured intermediates via two discrete pathways on a volcano-shaped FES.

scholarly journals Unraveling the structure and dynamics of the human DNAJB6b chaperone by NMR reveals insights into Hsp40-mediated proteostasis

2019 ◽  
Vol 116 (43) ◽  
pp. 21529-21538 ◽  
Author(s):  
Theodoros K. Karamanos ◽  
Vitali Tugarinov ◽  
G. Marius Clore
Keyword(s):  
Solution Structure ◽  
Specific Substrate ◽  
Monomeric Form ◽  
Linker Region ◽  
Structure And Dynamics ◽  
J Domain ◽  
Folded Proteins ◽  
High Flexibility ◽  
Interdomain Interactions ◽  
Shed Light

J-domain chaperones are involved in the efficient handover of misfolded/partially folded proteins to Hsp70 but also function independently to protect against cell death. Due to their high flexibility, the mechanism by which they regulate the Hsp70 cycle and how specific substrate recognition is performed remains unknown. Here we focus on DNAJB6b, which has been implicated in various human diseases and represents a key player in protection against neurodegeneration and protein aggregation. Using a variant that exists mainly in a monomeric form, we report the solution structure of an Hsp40 containing not only the J and C-terminal substrate binding (CTD) domains but also the functionally important linkers. The structure reveals a highly dynamic protein in which part of the linker region masks the Hsp70 binding site. Transient interdomain interactions via regions crucial for Hsp70 binding create a closed, autoinhibited state and help retain the monomeric form of the protein. Detailed NMR analysis shows that the CTD (but not the J domain) self-associates to form an oligomer comprising ∼35 monomeric units, revealing an intricate balance between intramolecular and intermolecular interactions. The results shed light on the mechanism of autoregulation of the Hsp70 cycle via conserved parts of the linker region and reveal the mechanism of DNAJB6b oligomerization and potentially antiaggregation.

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