A CGenFF‐based force field for simulations of peptoids with both cis and trans peptide bonds

Weiser, Laura J.; Santiso, Erik E.

doi:10.1002/jcc.25850

Cited by 34 publications

(59 citation statements)

References 59 publications

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“…The second of these challenges-force field accuracy-is arguably more difficult. There have been many attempts to parameterize all-atom force fields for peptoids 15,47,48 and other foldamers, 49,50 but the chemical diversity of peptidomimetics makes the development of a general-purpose force field for foldamers difficult. Here, we have opted to pursue a slightly different philosophy for foldamer simulation which utilizes our Bayesian Inference of Con-formational Populations (BICePs) algorithm.…”

Section: Methods and Resultsmentioning

confidence: 99%

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Hurley¹,

Northrup²,

Ge³

et al. 2021

Preprint

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<div>The rational design of foldable and functionalizable peptidomimetic scaffolds requires the concerted application of both computational and experimental methods. Recently, a new class of designed peptoid macrocycle incorporating spiroligomer proline mimics (Q-prolines) has been found to pre-organize when bound by monovalent metal cations. To determine the solution-state structure of these cation-bound macrocycles, we employ a Bayesian inference method (BICePs) to reconcile enhanced-sampling molecular simulations with sparse ROESY correlations from experimental NMR studies. The BICePs approach circumvents the need for bespoke force field parameterization, instead relying on experimental restraints to help narrow the possible set of cis/trans amide isomers in solution. Conformations predicted to be most populated in solution were then simulated in the presence of explicit cations to yield trajectories with observed binding events, revealing a highly-preorganized all-trans amide conformation, whose formation is likely limited by the slow rate of cis/trans isomerization. Interestingly, this conformation differs from a racemic crystal structure solved in the absence of cation. Free energies of cation binding computed from distance-dependent potentials of mean force suggest Na+ has higher affinity to the macrocycle than K+, with both cations binding much more strongly in acetonitrile than water. The simulated affinities are able to correctly rank the extent to which different macrocycle sequences exhibit preorganization in the presence of different metal cations and solvents, suggesting our approach is suitable for solution-state computational design.</div>

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Section: Methods and Resultsmentioning

confidence: 99%

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Hurley¹,

Northrup²,

Ge³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The replica temperatures are 300, 318, and 340 K, for the left, middle, and right replicas. The dihedral bias potential has the form

E_{dihe} ((), ω) goodbreak= goodbreak- \sum_{n = 1}^{4} K_{n} ((), 1 goodbreak+ \cos ((), 2 ω_{n} goodbreak- 180^{°}))

which has the same form as potentials used in this study 21,23 . The sum is over the four atom groups (CH n ‐C‐N‐CH n , CH n ‐C‐N‐R, O‐C‐N‐CH n , O‐C‐N‐R) that make up the ω dihedral.…”

Section: Methodsmentioning

confidence: 99%

“…The large rotational barrier presents a challenge for conventional molecular simulation and to properly sample cis and trans configurations requires an enhanced sampling method. Voelz and co‐workers 13,17 and Park and Szleifer 18 used replica exchange (RE) and Prakash et al, 19 Zhao et al, 20 and Weiser and Santiso 21 used metadynamics. Edison et al 22 used a method that scaled down the torsional barrier then increased it back to the full value at regular intervals.…”

Section: Introductionmentioning

confidence: 99%

Simulation studies of polypeptoids using replica exchange with dynamical scaling and dihedral biasing

Raubenolt

Rick

2022

J Comput Chem

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Polypeptoids differ from polypeptides in that the amide bond can more frequently adopt both cis and trans conformations. The transition between the two conformations requires overcoming a large energy barrier, making it difficult for conventional molecular simulations to adequately visit the cis and trans structures. A replica-exchange method is presented that allows for easy rotations of the amide bond and also an efficient linking to a high temperature replica. The method allows for just three replicas (one at the temperature and Hamiltonian of interest, a second high temperature replica with a biased dihedral potential, and a third connecting them) to overcome the amide bond sampling problem and also enhance sampling for other coordinates. The results indicate that for short peptoid oligomers, the conformations can range from all cis to all trans with an average cis/trans ratio that depends on side chain and potential model.

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“…A common way of developing atomistic peptoid forcefields is to fit from quantum mechanical calculations and validate against experiments. [ 20,54 ] Third, enhanced sampling calculations are demanding to properly sample the slow cis / trans isomerization of the backbone

ω

dihedrals. [ 20 ]…”

Section: Summary and Future Prospectsmentioning

confidence: 99%

Hierarchical assemblies of polypeptoids for rational design of advanced functional nanomaterials

Zhao

2021

Biopolymers

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Polypeptoids (poly‐N‐substituent glycines) are a class of highly tailorable peptidomimetic polymers. Polypeptoids have identical backbones as polypeptides (poly‐C‐substituent glycines), but sidechains of polypeptoids are appended to backbone nitrogen rather than α‐carbon of polypeptides. As a result, peptoid backbone lacks of chirality and hydrogen bond donors. This unique structure gives polypeptoids a combined merit of both high stability as synthetic polymers and biocompatibility as biopolymers. In addition, peptoid sequences can be engineered precisely to assemble specific crystalline patterns such as spheres, fibers, ribbons, tubes, and sheets, which shows promising potentials of polypeptoids for different applications such as antimicrobials, catalysts, drug delivery, and templating inorganic materials. In this review, we summarize recent investigations into hierarchical self‐assembly pathways and molecular structures of peptoid crystals that are of interest as templates for fabricating functional materials for potential biomedical, biochemical, and bioengineering applications. This review provides a summary of recent experimental and computational studies of polypeptoid assembly in solution and solid‐liquid interfaces, current achievements in the field, and discusses future challenges and opportunities for the rational design of self‐assembled polypeptoid nanomaterials.

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A CGenFF‐based force field for simulations of peptoids with both cis and trans peptide bonds

Cited by 34 publications

References 59 publications

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Simulation studies of polypeptoids using replica exchange with dynamical scaling and dihedral biasing

Hierarchical assemblies of polypeptoids for rational design of advanced functional nanomaterials

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