Mechanism of <i>β</i>‐hairpin formation in <scp>AzoChignolin</scp> and Chignolin

Zschau, Richard L; Zacharias, Martin

doi:10.1002/jcc.27059

Cited by 3 publications

(2 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ever-increasing computer power has recently allowed the routine performance of MD simulations with explicit solvent at the microsecond (μs) time scale to simulate the folding–unfolding transitions of fast-folding small peptides such as chignolin. ,, Different authors have reported MD studies with chignolin, focusing in the evaluation of simulation parameters (e.g., force fields, water models, and free energy landscape methods) and/or the folding thermodynamics of chignolin; ,,,,, however, none of them explored the pH dependence of the folding transition for the peptide. To provide a detailed picture of the peptide structure and dynamics in different protonation states, and thus, to better understand the kinetics and structural rearrangements experimentally observed, classical MD simulations were carried out at neutral and high pH (fully deprotonated peptide).…”

Section: Resultsmentioning

confidence: 99%

Folding Kinetics and Volume Variation of the β-Hairpin Peptide Chignolin upon Ultrafast pH-Jumps

Amado,

Chaves,

Cruz

et al. 2024

J. Phys. Chem. B

View full text Add to dashboard Cite

In-depth characterization of fundamental folding steps of small model peptides is crucial for a better understanding of the folding mechanisms of more complex biomacromolecules. We have previously reported on the folding/unfolding kinetics of a model α-helix. Here, we study folding transitions in chignolin (GYDPETGTWG), a short β-hairpin peptide previously used as a model to study conformational changes in β-sheet proteins. Although previously suggested, until now, the role of the Tyr2–Trp9 interaction in the folding mechanism of chignolin was not clear. In the present work, pH-dependent conformational changes of chignolin were characterized by circular dichroism (CD), nuclear magnetic resonance (NMR), ultrafast pH-jump coupled with time-resolved photoacoustic calorimetry (TR-PAC), and molecular dynamics (MD) simulations. Taken together, our results present a comprehensive view of chignolin's folding kinetics upon local pH changes and the role of the Tyr2–Trp9 interaction in the folding process. CD data show that chignolin's β-hairpin formation displays a pH-dependent skew bell-shaped curve, with a maximum close to pH 6, and a large decrease in β-sheet content at alkaline pH. The β-hairpin structure is mainly stabilized by aromatic interactions between Tyr2 and Trp9 and CH−π interactions between Tyr2 and Pro4. Unfolding of chignolin at high pH demonstrates that protonation of Tyr2 is essential for the stability of the β-hairpin. Refolding studies were triggered by laser-induced pH-jumps and detected by TR-PAC. The refolding of chignolin from high pH, mainly due to the protonation of Tyr2, is characterized by a volume expansion (10.4 mL mol–1), independent of peptide concentration, in the microsecond time range (lifetime of 1.15 μs). At high pH, the presence of the deprotonated hydroxyl (tyrosinate) hinders the formation of the aromatic interaction between Tyr2 and Trp9 resulting in a more disorganized and dynamic tridimensional structure of the peptide. This was also confirmed by comparing MD simulations of chignolin under conditions mimicking neutral and high pH.

show abstract

Section: Resultsmentioning

confidence: 99%

Folding Kinetics and Volume Variation of the β-Hairpin Peptide Chignolin upon Ultrafast pH-Jumps

Amado,

Chaves,

Cruz

et al. 2024

J. Phys. Chem. B

View full text Add to dashboard Cite

show abstract

“…Chignolin and CLN025 are among the most investigated fast-folding proteins concerning force field differences and testing various setups in computer simulations. ,,,, Due to their small size and distinct native conformation, they present fast-folding kinetics and hence are ideal candidates for examining protein folding. Characterizing the folding dynamics of Chignolin/CLN025 can facilitate the understanding of larger, biologically relevant systems and can consequently inform the design and development of new biotherapeutics.…”

Section: Discussionmentioning

confidence: 99%

The Role of Force Fields and Water Models in Protein Folding and Unfolding Dynamics

Fischer,

Tichy,

Kokot

et al. 2024

J. Chem. Theory Comput.

Self Cite

View full text Add to dashboard Cite

Protein folding is a fascinating, not fully understood phenomenon in biology. Molecular dynamics (MD) simulations are an invaluable tool to study conformational changes in atomistic detail, including folding and unfolding processes of proteins. However, the accuracy of the conformational ensembles derived from MD simulations inevitably relies on the quality of the underlying force field in combination with the respective water model. Here, we investigate protein folding, unfolding, and misfolding of fast-folding proteins by examining different force fields with their recommended water models, i.e., ff14SB with the TIP3P model and ff19SB with the OPC model. To this end, we generated long conventional MD simulations highlighting the perks and pitfalls of these setups. Using Markov state models, we defined kinetically independent conformational substates and emphasized their distinct characteristics, as well as their corresponding state probabilities. Surprisingly, we found substantial differences in thermodynamics and kinetics of protein folding, depending on the combination of the protein force field and water model, originating primarily from the different water models. These results emphasize the importance of carefully choosing the force field and the respective water model as they determine the accuracy of the observed dynamics of folding events. Thus, the findings support the hypothesis that the water model is at least equally important as the force field and hence needs to be considered in future studies investigating protein dynamics and folding in all areas of biophysics.

show abstract

Identification and Dynamics Understanding of Novel Inhibitors of Peptidase Domain of Collagenase G from Clostridium histolyticum

Anjum,

Hazazi,

Alsaeedi

et al. 2024

Computation

View full text Add to dashboard Cite

Clostridium histolyticum is a Gram-positive anaerobic bacterium belonging to the Clostridium genus. It produces collagenase, an enzyme involved in breaking down collagen which is a key component of connective tissues. However, antimicrobial resistance (AMR) poses a great challenge in combating infections caused by this bacteria. The lengthy nature of traditional drug development techniques has resulted in a shift to computer-aided drug design and other modern drug discovery approaches. The above method offers a cost-effective means for gathering comprehensive information about how ligands interact with their target proteins. The objective of this study is to create novel, explicit drugs that specifically inhibit the C. histolyticum collagenase enzyme. Through structure-based virtual screening, a library containing 1830 compounds was screened to identify potential drug candidates against collagenase enzymes. Following that, molecular dynamic (MD) simulation was performed in an aqueous solution to evaluate the behavior of protein and ligand in a dynamic environment while density functional theory (DFT) analysis was executed to predict the molecular properties and structure of lead compounds, and the WaterSwap technique was utilized to obtain insights into the drug–protein interaction with water molecules. Furthermore, principal component analysis (PCA) was performed to reveal conformational changes, salt bridges to express electrostatic interaction and protein stability, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) to assess the pharmacokinetics profile of top compounds and control molecules. Three potent drug candidates were identified MSID000001, MSID000002, MSID000003, and the control with a binding score of −10.7 kcal/mol, −9.8 kcal/mol, −9.5 kcal/mol, and −8 kcal/mol, respectively. Furthermore, Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) analysis of the simulation trajectories revealed energy scores of −79.54 kcal/mol, −73.99 kcal/mol, −62.26 kcal/mol, and −70.66 kcal/mol, correspondingly. The pharmacokinetics properties exhibited were under the acceptable range. The compounds hold the potential to be novel drugs; therefore, further investigation needs to be conducted to find out their anti-collagenase action against C. histolyticum infections and antibiotic resistance.

show abstract

Mechanism of β‐hairpin formation in AzoChignolin and Chignolin

Cited by 3 publications

References 49 publications

Folding Kinetics and Volume Variation of the β-Hairpin Peptide Chignolin upon Ultrafast pH-Jumps

Folding Kinetics and Volume Variation of the β-Hairpin Peptide Chignolin upon Ultrafast pH-Jumps

The Role of Force Fields and Water Models in Protein Folding and Unfolding Dynamics

Identification and Dynamics Understanding of Novel Inhibitors of Peptidase Domain of Collagenase G from Clostridium histolyticum

Contact Info

Product

Resources

About