Insights into Peptoid Helix Folding Cooperativity from an Improved Backbone Potential

Area of Science:

• Polymer Chemistry
• Computational Chemistry
• Biomolecular Modeling

Background:

• Peptoids (N-substituted oligoglycines) are versatile biomimetic polymers capable of forming diverse structural scaffolds.
• Peptoid helices, characterized by bulky chiral side chains, are a crucial motif whose accurate simulation remains a challenge.

Purpose of the Study:

• To develop and validate a molecular simulation approach for accurately modeling peptoid helix formation.
• To investigate the molecular forces governing the cooperative folding of N-substituted oligoglycines (Nspe) helices.

Main Methods:

• Modification of the backbone φ-angle potential in the GAFF force field.
• Validation using Quantum Mechanics (QM) calculations and Nuclear Magnetic Resonance (NMR) experiments.
• Quantitative comparison with Nuclear Overhauser Effect (NOE) data using the Bayesian Inference of Conformational Populations (BICePs) algorithm.
• Extensive Replica Exchange Molecular Dynamics (REMD) simulations and Lifson-Roig helix-coil theory analysis.

Main Results:

• A modified GAFF potential accurately reproduces Nspe cis-amide helices, consistent with experimental data.
• REMD simulations and helix-coil theory analysis indicate significantly more cooperative folding of Nspe helices with the modified potential.
• Per-residue entropy changes suggest steric bulk, rather than hydrogen bonding, is the primary driving force for peptoid helix nucleation and extension.

Conclusions:

• The modified simulation potential enables accurate modeling of peptoid helix formation.
• Steric bulk is identified as the key factor driving cooperative helix folding in Nspe oligomers.
• Findings will aid in predicting and designing novel peptoid-based peptidomimetics and complex assemblies.