Quantifying Polypeptoid Conformational Landscapes through Integrated Experiment and Simulation

Abstract

We combine experiment and simulation to develop a powerful, validated approach for characterizing the conformational landscapes of disordered polypeptoids. Polypeptoids have become an important class of polymers, capable of precisely defined sequences while remaining gram-synthesizableproperties that have driven a rapidly expanding set of applications, including antifoulants, therapeutics, sensing, and directed self-assembly. The characterization of polypeptoid structure provides critical molecular insight into sequence−structure−function relationships. Structurally disordered polypeptoids require new approaches to interrogate their wide range of conformations in solution. Here, we measure full end-to-end distance distributions, instead of configurational averages, using double electron−electron resonance (DEER) spectroscopy and enhanced sampling molecular modeling. We demonstrate excellent agreement between the experiments and simulations for a set of model hydrophilic polypeptoids. Moreover, we illustrate the utility of this combined experiment−simulation approach in probing structure−function relationships by characterizing the basic polymer physics of this polypeptoid series, demonstrating that the polypeptoids probed here exhibit excluded volume behavior.

Sequence Modulates Polypeptoid Hydration Water Structure and Dynamics

“…Lennard-Jones nonbonded interactions are cut off at 10 Å. Hydrogen bonds are constrained with SHAKE, 35 and water is kept rigid with SETTLE. 36 We first run a simulation in an expanded ensemble over softened ω dihedral states, a technique we previously developed and validated that samples across slow isomerizations in the polypeptoid backbone, 31 using Langevin dynamics with an integration timestep of 2 fs, a temperature of 300 K, and a friction coefficient of 0.01 ps −1 . The pressure is set to 1 bar using a Monte Carlo (MC) barostat with 500 fs between MC barostat moves.…”

“…The peptoid sequences chosen are discussed at the beginning of Section . We use the MFTOID forcefield, which we have previously shown accurately captures the experimentally measured structural distributions of disordered polypeptoids, such as the ones we study here . To prepare the system, we create and geometry-minimize initial peptoid structures in the fully extended conformation using Avogadro 1.2.0 .…”

“…Polypeptoids are highly tunable molecules, as they can be synthesized sequence-specifically via a process that allows access to a wide variety of chemistries. , Previous computational efforts have begun to examine water behavior near polypeptoids in solution and at surfaces, , but have been hampered by slow isomerization timescales (seconds) in polypeptoids that are inaccessible to molecular dynamics simulation. Here, we leverage a computational workflow that accurately samples polypeptoid conformational landscapes in solution to probe the effects of the polypeptoid sequence on local water behavior. We first examine the effect of an entirely polar peptoid sequence on hydration water behavior, making comparisons to bulk water (Section ).…”

Where Biology and Traditional Polymers Meet: The Potential of Associating Sequence-Defined Polymers for Materials Science

“…In this example, double electron–electron resonance (DEER) probes distributions of end-to-end distances of polypeptoids with different numbers of repeat units. Reproduced from ref ( 84 ). Copyright 2021 American Chemical Society.…”

“…Potential approaches for achieving detailed sequence-structure insights include borrowing methods from biophysics that allow probes to be installed in specific sites along a polymer chain that can then leverage, for example, nuclear magnetic resonance (NMR), , fluorescence methods, or electron paramagnetic resonance (EPR) , to probe distributions of distances in polymer chains (Figure a). Of these methods, 2D NMR is unique in that it can determine the structure of small proteins without the use of labels, but extension to longer molecules is made challenging by loss of resolution and increasingly convoluted spectra.…”