Wait, Did You Just Say Force Field?

New work builds on research to make bio-inspired plastics that could sense and degrade chemical and biological agents, ultimately saving the lives of warfighters, first responders and civilians.

Scientists have now developed the capability to accurately predict the three-dimensional (3-D) structure of peptoids (peptide resembling constructs), which is a critical capability for devising these robust functional materials.

Figures: A) Differences between positional isomers: in peptoids functional sidechains are attached to backbone nitrogens (depicted in green), whereas in peptides they are attached to α-carbons (depicted in light blue-green); Φ and ψ represent two dihedral angles. B) Force field simulations provide to obtain free energy landscapes.  (Courtesy photo provided by the Defense Threat Reduction Agency's Chemical and Biological Technologies Department)

Figures: A) Differences between positional isomers: in peptoids functional sidechains are attached to backbone nitrogens (depicted in green), whereas in peptides they are attached to α-carbons (depicted in light blue-green); Φ and ψ represent two dihedral angles. B) Force field simulations provide to obtain free energy landscapes. (Courtesy photo provided by the Defense Threat Reduction Agency’s Chemical and Biological Technologies Department)

Eventually, these materials will be used in sensing, decontamination and protection measures. 

In a recent Journal of Computational Chemistry article titled “Development and use of an atomistic CHARMM-based force field for peptoid simulation,” the scientific team lead by Drs. Ronald Zuckermann and Stephen Whitelam of the Molecular Foundry at Lawrence Berkeley National Laboratory developed and validated a first-generation force field to enable accurate molecular dynamics simulations of peptoid oligomers and polymers.

Force.  Field.

The force field, which the team named MFTOID (pronounced: em-eff-toyd), after “Molecular Foundry” and “peptoid,” is now freely available.

It is compatible with the CHARMM (Chemistry at HARvard Macromolecular Mechanics) platform, which is commonly used for peptides, proteins, DNA, RNA and lipids.

This is a major step forward that significantly boosts the science of protein-mimetic polymer design and builds on Zuckermann’s previous work to make biomimetic functional plastics (see the article “Biomimetic Functional Plastics Sense and Degrade Chem Bio Threats” from December 2012’s JSTO in the News).

Because there are significant structural differences between peptides and peptoids, it is not possible to perform accurate structure predictions using the well-established peptide force fields.

In a multi-year effort, this team derived a custom force field for the peptoid backbone from first principles, using as target data quantum mechanical calculations and the experimental thermodynamic properties of simple tertiary amide model compounds.

These force fields enable scientists to accurately predict the conformation of peptoid chains for the first time. The chemical synthesis of peptoid polymers is well established, but the scientific community has been lacking the tools, until now, to be able to rationally design folded peptoid polymers.

The force field parameters developed here can be used to understand the atomic-scale 3-D structure of self-assembled peptoids.

They will allow us to engineer peptoid assemblies, like the peptoid nanosheets, to introduce new functionalities, such as creating customized “active sites” for molecular recognition and catalysis, and to improve their stability. The computational tools developed here will allow the building of peptoid nanostructures with the same level of precision that is typically performed with proteins.

The combination of these computational tools with the already established peptoid synthesis capabilities promises to be a very powerful package to design rugged protein-mimetic nanostructures.

The future research plan includes strategic incorporation of appropriate functional groups to achieve desired functionalities, such as specific affinity binding and catalysis.

Functionalized peptoids can be the basis for a new generation of robust binders, catalysts, antimicrobials, therapeutics, and nanomaterials for Department of Defense applications in sensing, decontamination, and protection.

Story and information by John Davis
Defense Threat Reduction Agency’s Chemical and Biological Technologies Department

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