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

Abstract

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 preorganize 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 to predict and design conformational and binding properties of macrocycles as functional scaffolds for peptidomimetics. 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 a 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.

Development of a Systematic and Extensible Force Field for Peptoids (STEPs)

“…It is worth noting that multiple force fields are available in the protein space, but that field is significantly more developed and studied. Despite this higher bar to entry, peptoid simulation papers include at least 19 GAFF-based, ,,− 13 MFTOID-, ,− 11 CHARMM-, or CGenFF-based, − 3 PEPDROID-based, − and other computational studies. − One particularly noteworthy effort was the development of a peptoid rotamer library containing over 50 side chains in the structural prediction tool ROSETTA based on CHARMM peptide parameters. , …”

BICePs v2.0: Software for Ensemble Reweighting Using Bayesian Inference of Conformational Populations

“…A summary of the theory of BICePs, and a discussion of closely related methods, can be found in a recent review article . To date, BICePs has been applied to a number of molecular systems ranging from small macrocycles, ,, to peptides and peptidomimetics, − and larger proteins like apomyoglobin …”

“…A summary of the theory of BICePs, and a discussion of closely related methods, can be found in a recent review article. 24 To date, BICePs has been applied to a number of molecular systems ranging from small macrocycles, 11,30,31 to peptides and peptidomimetics, 32−34 and larger proteins like apomyoglobin. 35 Despite the availability of BICePs, and many published examples of its use, researchers may still find it difficult to apply to their system of interest.…”

Minimal Peptoid Dynamics Inform Self-Assembly Propensity

“…Voelz et al then performed a survey of AMBER force fields to assess which was best suited for the simulation of peptoids, by comparing the replication of low torsional minima from QM data obtained by Butterfoss et al and experimental determined structures . The Generalized Amber Force Field (GAFF) performed best, an additional biasing potential was required to reproduce the correct φ torsion preference in Nfes residues, and subsequently this was successfully employed in de novo structure prediction of small peptoid molecules and the simulation of metal cation binding in Q-proline macrocycles. , Mukherjee et al also modified this force field for improved simulation of peptoid helices to reproduce QM and experimental results . This modified force field, dubbed GAFF-φ (also known as GAFF2), has subsequently been used to simulate porphyrin-modified peptoid helices and reproduce experimentally observed changes in helical structure .…”