A DFT study of structure and stability of pleated and rippled cross-β sheets with hydrophobic sidechains

Significance 

Since discovering the pleated cross-β framework in 1951, it has remained a topic of interest amongst researchers. Pleated cross-β sheets comprise polypeptide chains arranged in a two-dimensional (2D) network. The polypeptides can be arranged in either parallel or antiparallel to form two topographies. Subsequent studies have resulted in numerous pleated cross-β frameworks. The most significant contribution is extending the pleated cross-β framework to form rippled cross-β sheets considering amino acid chirality variables. Therefore, they can also be arranged in parallel and antiparallel format to produce parallel rippled cross-β sheets and antiparallel rippled cross-β sheets, respectively. Unlike their pleated counterparts, rippled cross-β sheets exhibit chirality variation property.

Pleated cross-β topographies have been extensively studied. Several theoretical and experimental studies demonstrating the structures of pleated cross-β motifs have been reported. However, studies on the rippled cross-β patterns are scarce despite its potential practical implications. Based on the literature, the few studies about rippled cross-β framework provide useful insights for advancing future studies on the subject. For instance, the latest experiments have demonstrated that rippled cross-β sheets are likely to be favored over pleated cross-β sheets due to peptides with different sizes that are more susceptible to the diverse racemic mixtures of aggregation. Additionally, hydrogel-forming peptides exhibit an improvement in the rigidity and thermodynamic stability when mirror-image peptides are used. Unfortunately, systematic studies from the beginning are still lacking, and there are no rules to guide the design and formulation of rippled cross-β frameworks.

Rippled cross-β sheets have recently emerged as a promising design method for novel materials and related applications. As such, intensive study on their structure and properties is urgent. On this account, Professor Jevgenij A. Raskatov from the University of California Santa Cruz investigated the stability and structure of the pleated and rippled cross-β sheets with hydrophobic sidechains using DFT computational methods. A series of model systems were designed, and the cross-β dimers were developed from the previously reported Pauling-Corey coordinates. The author performed DFT calculations to determine and understand the impact of bulky hydrophobic amino acid sidechains on the design and preparation of rippled and pleated cross-β topographies. The work is published in the journal, Biopolymers.

Results showed that both the rippled parallel and pleated parallel cross-β-5 X 2 systems exhibited isoenergetic behavior in water. However, the pleated parallel was preferred in vacuo due to its ability to alleviate the steric strain. On the other hand, pleated parallel cross-β-5 X 3 systems, created by adding an extra layer in the fibril dimension, exhibited an out-of-plane distortion similar to that of cross-β-5 X 2, while it’s the rippled one remained flat. It was necessary to geometry-optimize the structures to eliminate the geometric constraints such as frozen atoms and angles to enhance the accuracy of the results. Due to the less sterically constrain of the individual peptide sidechains in rippled fashion, rippled cross-β systems displayed higher sidechain entropy and stability than pleated counterparts.

In summary, DFT computational methods were used to study the effects of the bulky amino acid sidechains on the pleated and rippled cross-β model systems. The results revealed some long-range features that arise due to H-bonding in both rippled and plateau cross-β sheets and how they can be recapitulated through trimetric model. The high preference for rippled over pleated topography could be attributed to lower steric bulk. Moreover, the distortions in the cross-β-5 X 3 parallel frameworks were similar for both Val and tBu and were likely to be the case with other hydrophobic amino acids. In a statement to the Advances in Engineering, Professor Raskatov explained his study would advance general frameworks for designing rippled cross cross-β topographies suitable for different practical applications.

A DFT study of structure and stability of pleated and rippled cross-β sheets with hydrophobic sidechains - Advances in Engineering

About the author

Jevgenij Raskatov was born in Moscow on 03.03.1981 and grew up as a professional musician. Following the family move to Germany in 1994, he eventually studied Chemistry at the University of Heidelberg. In 2006 he moved to Oxford to pursue his graduate studies in Physical Organic Chemistry with focus on asymmetric catalysis and chiral ion pairing. In 2009 he went to Caltech, where he worked on gene regulation via DNA-binding Py-Im polyamides under mentorship of Peter Dervan.

Raskatov started his independent research career at UCSC in 2014. He focused his attention on Amyloid β (Aβ): the aggregation-prone peptide and a key toxic agent of Alzheimer’s Disease. The Raskatov lab devised Aβ Chiral Inactivation (Aβ-CI) as an oligomer-to-fibril conversion method to block Aβ neurotoxicity (Angew. Chem. Int. Ed. 2017, 56, 11506). Subsequent mechanistic investigations led the Raskatov lab to the “Rippled Sheet”: a structural class that was predicted in 1953 by Pauling and Corey. The Rippled Sheet is a structural motif that has generality comparable with the α-Helix. It holds immense potential for applications in the realm of biomaterials (Acc. Chem. Res. 2021, 54, 2488).

Reference

Raskatov, J. (2020). A DFT study of structure and stability of pleated and rippled cross‐β sheets with hydrophobic sidechainsBiopolymers, 112(1), 1-6.

Go To Biopolymers

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