It’s how you move that matters – studying protein vibrations

giphy (1)

Molecular interactions resemble a dance, a composition of energy and motion.

A novel tool that may provide fresh perspectives to structural biologists has been developed by Dr Andrea Markelz’s group from the University of Buffalo. Its application towards understanding a biological function was published in  “Moving in the Right Direction: Protein Vibrational Steering Function” in the Biophysical Journal, with Dr Katherine Niessen as first author.

The group developed a technique called anisotropic terahertz microscopy (ATM) which was able to distinguish directional motions of protein vibrations. This is opposed to traditional methods that only measure total vibrational energy distribution by neutron inelastic scattering.

One way distal mutations (i.e. mutations far away from the site of disruption) affect ligand (i.e. drug/protein/other molecule) binding is by inducing long-range motions in protein structure that allows accommodation of the ligand. This technique could therefore provide a fresh look at drug-protein interactions, allowing scientists to discern and model drugs that not only bind but produce the desired vibrations to cause a particular effect.

Niessen et al. demonstrated the utility of ATM by studying the chicken egg white lysozyme (CEWL) and its binding to inhibitor (tri-N-acetyl-D-glucosamine, 3NAG). Binding of the inhibitor did not produce much change in the vibrational density of states (VDOS or energy distribution) whereas ATM could detect dramatically different changes between bound and unbound states.

They attributed these differences to the direction of vibrational movement. By computer modelling and simulation, the unbound (apo) form exhibited clamping motions around the binding site while the bound (holo) form displayed more twisting motions. Quite a stark difference when you consider the dance moves in “Heyyy Macarena” from “Twist and Shout”.

Furthermore, CEWL with distal mutations that induced higher catalytic activity without changes in binding, saw no significant change in VDOS but distinct differences in anisotropic absorbance. This demonstrates the utility of ATM to evaluate long-range mutations and their effect on protein activity.

Challenges remain as highlighted by Dr Jeremy Smith, a key expert in the field. This involves the need to crystallize and align proteins, and evaluating the detection sensitivity of the technique on a range of vibration types and under various conditions. But even he agreed it was a step (or shimmy) in the right direction.

 

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