Illuminating the dark conformational space of macrocycles using dominant rotors

Diaz, Diego B.; Appavoo, Solomon D.; Bogdanchikova, Anastasia F.; Lebedev, Yury; McTiernan, Timothy John; Gomes, Gabriel; Yudin, Andrei K.

doi:10.1038/s41557-020-00620-y

Cited by 42 publications

(38 citation statements)

References 64 publications

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“…This approach can therefore be related to other synthetic appendages used to induce peptide conformations, e.g. molecular rotors, 13 or α-helix staples. 14 It also relates to the observation that natural macrocyclic peptides are the object of multiple biosynthetic modifications that expand their functions beyond what can be achieved with proteinogenic α-amino acids only.…”

Section: Introductionmentioning

confidence: 99%

Conformational interplay in hybrid peptide–helical aromatic foldamer macrocycles

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Conformational interplay in hybrid peptide–helical aromatic foldamer macrocycles

et al. 2021

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“…Yudin et al reported an unusual tunable atropisomeric peptidyl macrocycle which is made possible by controlling the conformational interconversion. 3 More recently, Baran and co-workers accomplished the reported total synthesis of the peptidic indole alkaloid tryptorubin A and defined "non-canonical atropisomers", a family of shape-defined molecules that are distinguished by bridge below/bridge above arrangements (Fig. 1c) 4 .…”

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confidence: 99%

The occurrence of ansamers in the synthesis of cyclic peptides

Yao

Kosol

Wenz

et al. 2022

Preprint

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α-Amanitin is a bicyclic octapeptide composed of a macrolactam with a tryptathionine cross-link forming a handle. Previously, the occurrence of isomers of amanitin, termed atropisomers has been postulated. Al-though the total synthesis of α-amanitin has been accomplished this aspect still remained unsolved. We performed the synthesis of amanitin analogues, accompanied by in-depth spectroscopic, crystallographic and molecular dynamics studies. The data unambiguously confirmed the synthesis of two amatoxin-type isomers, for which we propose the term ansamers. The natural structure of the P-ansamer can be ansa-selectively synthesized using an optimized synthetic strategy. We believe that the newly described terminology does also have implications for many other peptide structures, e.g. norbornapeptides, lasso peptides, tryptorubins and others, and helps to unambiguously describe conformational isomery of cyclic peptides.

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“…This choice of training set properties is justified by the potential target applications of small basis set HF based methods, namely fast geometry optimizations and non-covalent interaction strengths in large systems as well as high-throughput 87 screening of conformers in combination with conformer search techniques [88][89][90] . These applications are useful, for instance, when performing exhaustive conformational searches of macrocyclic drugs [91][92][93][94][95][96] and other pharmaceutical candidates 97 , and studying biochemical processes like protein folding [98][99][100] and puckering of nucleotides 101,102 .…”

Section: Training and Validation Data Setsmentioning

confidence: 99%

Fast and accurate quantum mechanical modeling of large molecular systems using small basis set Hartree–Fock methods corrected with atom-centered potentials

Prasad

Otero-de-la-Roza

DiLabio

2022

Preprint

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There has been significant interest in developing fast and accurate quantum mechanical methods for modeling large molecular systems. In this work, by utilizing a machine-learning regression technique, we have developed new low-cost quantum mechanical approaches to model large molecular systems. The developed approaches rely on using one-electron Gaussian-type functions called atom-centered potentials (ACPs) to correct for the basis set incompleteness and the lack of correlation effects in the underlying minimal or small basis set Hartree-Fock (HF) methods. In particular, ACPs are proposed for ten elements common in organic and bio-organic chemistry (H, B, C, N, O, F, Si, P, S, and Cl) and four different base methods: two minimal basis sets (MINIs and MINIX) plus a double-ζ basis set (6-31G*) in combination with dispersion-corrected HF (HF-D3/MINIs, HF-D3/MINIX, HF-D3/6-31G*), and the HF-3c method. The new ACPs are trained on a very large set (73832 data points) of non-covalent properties (interaction and conformational energies) and validated additionally on a set of 32048 data points. All reference data is of complete basis set coupled-cluster quality, mostly CCSD(T)/CBS. The proposed ACP-corrected methods are shown to give errors in the tenths of a kcal/mol range for non-covalent interaction energies and up to 2 kcal/mol for molecular conformational energies. More importantly, the average errors are similar in the training and validation sets, confirming the robustness and applicability of these methods outside the boundaries of the training set. In addition, the performance of the new ACP-corrected methods is similar to complete basis set DFT but at a cost that is orders of magnitude lower, and the proposed ACPs can be used in any computational chemistry program that supports effective-core potentials without modification. It is also shown that ACPs improve the description of covalent and non-covalent bond geometries of the underlying methods and that the improvement brought about by the application of the ACPs is directly related to the number of atoms to which they are applied, allowing the treatment of systems containing some atoms for which ACPs are not available. Overall, the ACP-corrected methods proposed in this work constitute an alternative accurate, economical, and reliable quantum mechanical approach to describe the geometries, interaction energies, and conformational energies of systems with hundreds to thousands of atoms.

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Illuminating the dark conformational space of macrocycles using dominant rotors

Cited by 42 publications

References 64 publications

Conformational interplay in hybrid peptide–helical aromatic foldamer macrocycles

Conformational interplay in hybrid peptide–helical aromatic foldamer macrocycles

The occurrence of ansamers in the synthesis of cyclic peptides

Fast and accurate quantum mechanical modeling of large molecular systems using small basis set Hartree–Fock methods corrected with atom-centered potentials

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