Sequence-based prediction of the solubility of peptides containing non-natural amino acids

Abstract

Non-natural amino acids are increasingly used as building blocks in the development of peptide-based drugs, as they expand the available chemical space to tailor function, half-life and other key properties. However, while the chemical space of modified amino acids (mAAs) is potentially vast, experimental methods for measuring the developability properties of mAA-containing peptides are expensive and time consuming. To facilitate developability programs through computational methods, we present CamSol-PTM, a method that enables the fast and reliable sequence-based prediction of the solubility of mAA-containing peptides. From a computational screening of 50,000 mAA-containing variants of three peptides, we selected five different mAAs for a total number of 30 peptide variants for experimental validation. We demonstrate the accuracy of the predictions by comparing the calculated and experimental solubility values. Our results indicate that the computational screening of mAA-containing peptides can extend by over four orders of magnitude the ability to explore the solubility chemical space of peptides. This method is available as a web server athttps://www-cohsoftware.ch.cam.ac.uk/index.php/camsolptm.

Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments

“…The comparison of the SASA of the whole structure of the two Aβ42 filaments types with respect to the SASA of the Aβ42 monomer in solution (41) indicates that the hydrophobic region in the C-terminus region of the protein (37)(38)(39)(40)(41)(42) is not exposed to the solvent in type I filaments (Figure 3A), generating a more soluble filament (Figure 4A), according to the structurally-corrected CamSol solubility score (42,43). Instead in the type II filaments it remains exposed to the solvent (Figure 3B), generating a more insoluble filament (Figure 4B, red box).…”

Carbon nanotubes functionalized with α-aminoisobutyric acid-containing peptide increase gene delivery efficiency in plant mitochondria

“…1a, b). The residues for substitution were selected based on their hydrophobicity to increase their intracellular solubility to improve functionalization [30,31]. Furthermore, the substitution of Aib within peptides has been previously demonstrated to promote and stabilize helical structures due to the additional dimethyl group integrated as part of the peptide backbone; our previous research has also demonstrated that such substitutions have also worked efficiently at improving the translocation of substituted peptides through the translocase of the outer membrane (TOM) complex in plant cells [19].…”

From Canonical to Unique: Extension of A Lipophilicity Scale of Amino Acids to Non-Standard Residues

“…[13] Such efforts have led to novel structure/activity studies on modified peptides that present chemoinformatics tools to efficiently characterize the chemical space of these new peptides and thereby better understand their activities, e.g., their antimicrobial activity against multidrug-resistant bacteria. [14] In the context of the lipophilicity for non-canonical amino acids, prominent examples highlighting the significance and relevance of this topic include recent studies by Kubyshkin (2021) [15] and Oeller et al (2023). [16] The computational work of Oeller et al introduced the CamSol-PTM tool, which offers a rapid and accurate methodology for predicting the solubility of peptides containing non-standard amino acids.…”

“…[14] In the context of the lipophilicity for non-canonical amino acids, prominent examples highlighting the significance and relevance of this topic include recent studies by Kubyshkin (2021) [15] and Oeller et al (2023). [16] The computational work of Oeller et al introduced the CamSol-PTM tool, which offers a rapid and accurate methodology for predicting the solubility of peptides containing non-standard amino acids. Regarding to the experimental work of Kubyshkin, it aimed to develop an experimental lipophilicity https://doi.org/10.26434/chemrxiv-2024-8smwg ORCID: https://orcid.org/0000-0003-4029-4528 Content not peer-reviewed by ChemRxiv.…”