Peptide Bond Isomerization in High-Temperature Simulations

Neale, Chris; Pomès, Régis; Garcı́a, Angel E.

doi:10.1021/acs.jctc.5b01022

Cited by 20 publications

(14 citation statements)

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“…We then simulated the cis and trans conformations separately by replica exchange MD to investigate the stability of the complex when P20 is either in the trans or the cis state. Within the simulated time and at the chosen temperatures, the simulations do not sample prolyl isomerization, as expected 36 (Supplementary Fig. 7 ).…”

Section: Resultssupporting

confidence: 52%

A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction

et al. 2018

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The interactions of intrinsically disordered proteins (IDPs) with their molecular targets are essential for the regulation of many cellular processes. IDPs can perform their functions while disordered, and they may fold to structured conformations on binding. Here we show that the cis/trans isomerization of peptidyl−prolyl bonds can have a pronounced effect on the interactions of IDPs. By single-molecule spectroscopy, we identify a conserved proline residue in NCBD (the nuclear-coactivator binding domain of CBP) whose cis/trans isomerization in the unbound state modulates the association and dissociation rates with its binding partner, ACTR. As a result, NCBD switches on a time scale of tens of seconds between two populations that differ in their affinities to ACTR by about an order of magnitude. Molecular dynamics simulations indicate as a cause reduced packing of the complex for the cis isomer. Peptidyl-prolyl cis/trans isomerization may be an important previously unidentified mechanism for regulating IDP interactions.

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Section: Resultssupporting

confidence: 52%

A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction

et al. 2018

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“…Transitions involving peptide bond isomerization, from cis to trans configurations, are the slowest, with characteristic time scales of milliseconds or longer at low temperatures. In agreement with the findings of Garcia and co-workers, 108 we observe that temperatures greater than ≈350.0 K will be required to allow bond isomerizations on the submillisecond time scale. Both the C 7 ax → C 5 and the cis → trans transition times seem to be unaffected by the presence of a polar side-chain in Ac-Ser-NH 2 .…”

Section: Resultssupporting

confidence: 92%

“… 107 Therefore, at physiological conditions, the cis configurations will not contribute significantly to the global thermodynamics, and peptide bond isomerizations will only occur at elevated temperatures. 107 , 108 …”

Section: Resultsmentioning

confidence: 99%

Side-Chain Polarity Modulates the Intrinsic Conformational Landscape of Model Dipeptides

2021

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The intrinsic conformational preferences of small peptides may provide additional insight into the thermodynamics and kinetics of protein folding. In this study, we explore the underlying energy landscapes of two model peptides, namely, Ac-Ala-NH 2 and Ac-Ser-NH 2 , using geometry-optimization-based tools developed within the context of energy landscape theory. We analyze not only how side-chain polarity influences the structural preferences of the dipeptides, but also other emergent properties of the landscape, including heat capacity profiles, and kinetics of conformational rearrangements. The contrasting topographies of the free energy landscape agree with recent results from Fourier transform microwave spectroscopy experiments, where Ac-Ala-NH 2 was found to exist as a mixture of two conformers, while Ac-Ser-NH 2 remained structurally locked, despite exhibiting an apparently rich conformational landscape.

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“…Both starting structures contained all peptide bonds in the trans state. Recently published work using the same extended and NMR starting structures, but using the REMD enhanced sampling method, did not capture any cis sampling ( Gerlach et al, 2020 ), which is consistent with other studies that show REMD is not an effective method for observing proline isomerization ( Yedvabny et al, 2014 ; Neale et al, 2016 ; Zosel et al, 2018 ).…”

Section: Resultssupporting

confidence: 84%

An Unbound Proline-Rich Signaling Peptide Frequently Samples Cis Conformations in Gaussian Accelerated Molecular Dynamics Simulations

Alcantara

Stix

Huang

et al. 2021

Front. Mol. Biosci.

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Disordered proline-rich motifs are common across the proteomes of many species and are often involved in protein-protein interactions. Proline is a unique amino acid due to the covalent bond between the backbone nitrogen and the proline side chain. The resulting five-membered ring allows proline to sample the cis state about its peptide bond, which other residues cannot do as readily. Because proline-rich disordered sequences exist as ensembles that likely include structures with the proline peptide bond in cis, a robust methodology to accurately account for these conformations in the overall ensemble is crucial. Observing the cis conformations of proline in a disordered sequence is challenging both experimentally and computationally. Nitrogen-hydrogen NMR spectroscopy cannot directly observe proline residues, which lack an amide bond, and computational methods struggle to overcome the large kinetic barrier between the cis and trans states, since isomerization usually occurs on the order of seconds. In the current work, Gaussian accelerated molecular dynamics was used to overcome this free energy barrier and simulate proline isomerization in a tetrapeptide (KPTP) and in the 12-residue proline-rich SH3 binding peptide, ArkA. We found that Gaussian accelerated molecular dynamics, when combined with a lowered peptide bond dihedral angle potential energy barrier (15 kcal/mol), allowed sufficient sampling of the proline cis and trans states on a microsecond timescale. All ArkA prolines spend a significant fraction of time in cis, leading to a more compact ensemble with less polyproline II helix structure than an ArkA ensemble with all peptide bonds in trans. The ensemble containing cis prolines also matches more closely to in vitro circular dichroism data than the all-trans ensemble. The ability of the ArkA prolines to isomerize likely affects the peptide’s ability to bind its partner SH3 domain, and should be studied further. This is the first molecular dynamics simulation study of proline isomerization in a biologically relevant proline-rich sequence that we know of, and a similar protocol could be applied to study multi-proline isomerization in other proline-containing proteins to improve conformational diversity and agreement with in vitro data.

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Peptide Bond Isomerization in High-Temperature Simulations

Cited by 20 publications

References 100 publications

A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction

A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction

Side-Chain Polarity Modulates the Intrinsic Conformational Landscape of Model Dipeptides

An Unbound Proline-Rich Signaling Peptide Frequently Samples Cis Conformations in Gaussian Accelerated Molecular Dynamics Simulations

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