Structural biology explores the molecular structure of biological macromolecules such as proteins and nucleic acids and provides key insights into the biological reactions that fuel life. The field in part asks, How are biological molecules created?

Scientists use imaging technology to view molecules in three dimensions to understand assembly function and interaction. Structural biologists can’t see the biomolecules on which they work even with the most advanced light microscopes. Structural biologists, therefore, must use measurements on vast numbers of identical molecules at the same time to determine a structure. Advances in software, through the use of virtual reality and other new technologies, could transform this field of drug discovery.

Researchers use techniques such as mass spectrometry, macromolecular crystallography, proteolysis, nuclear magnetic resonance spectroscopy of proteins (NMR), electron paramagnetic resonance (EPR), cryo-electron microscopy (cryo-EM), multiangle light scattering, small angle scattering, ultrafast laser spectroscopy, dual-polarization interferometry, and circular dichroism.

Read more: Why Structural Biologists Love 3D Molecular Visualization in Virtual Reality

Researchers have illuminated the structure of over 122,000 proteins, stored on public databases such as RCSB Protein Data Bank. Structural biology research has led to new medical treatments for misshapen molecules.

Structural biologists, who are mostly focused on proteins due to their central role in the body, often seek to understand through their research the form and function of large molecules composed of RNA-protein complexes.

Structural Biologists today can exploring Hemoglobin in virtual reality

What Structural Biologists Do

Researchers have used the insights of structural biology to understand why proteins fold, and how amino acids interact. Researchers have even designed their own proteins that serve very specific jobs.

In structure-based drug design, scientists outline a protein to base new medicines off it. The resulting drugs usually work by blocking or aiding the functioning of certain proteins in the body. Oftentimes, computerized models of protein structures help them visualize how proteins function in concert. Scientists might be working on a new molecule that blocks or changes a specific interaction between two proteins so as to turn back disease. The structural biology and molecular modeling techniques market could improve the medicines which doctors prescribe.

History of Structural Biology

“In the 1950s the biochemical world had no information about the molecular structure of globular proteins and enzymes,” writes Leonard J. Banaszak in his book Foundations of Structural Biology. “Even protein characterization procedures, which today can be done in a matter of minutes, were then very complex. For example, a now simple task such as determining the molecular weight of a protein was a major undertaking. Most often it necessitated of an analytical ultracentrifuge and other physical-chemical measurements.”

Exploring proteins in VR

That work could take months. Scientists also didn’t know as much as they do today about amino acid sequences, which make up protein molecules, and the techniques for analyzing amino acid sequences were still unrefined.

Availability of the first amino acid analyzers, which involve a technique based on ion exchange liquid chromatography and is used in a wide range of application areas to provide qualitative and quantitative compositional analysis, didn’t help much at first, since scientists still had to wait years to procure chemical sequences.

“On the structural side, there was essentially no information on protein conformation,” writes Banaszak. This changed in the mid-1930s thanks to the studies of physicist Sir Lawrence Bragg, Jr. Max Perutz on the structure hemoglobin.

“The revolution that has taken place in the biological and medical sciences during the last half of the twentieth century surpasses the developments in other areas of the physical sciences by a significant margin,” Banaszak wrote in the year 2000. “A notable part of this quantum leap is due to the advances in structural biology.”

Throughout the nineties, even more so in the 21st century, it has become increasingly easy to interpret three-dimensional information.

“To link structural and biological properties, the scientist must be able to visualize the conformations and the fidelity and flexibility of the macromolecules are complex,” writes Banaszak. “There are only a few ways to make visualization feasible.”

In order to accurately determine the structure of a molecule, the structural biologist must be able to see the molecule in three dimensions.

“This can be done with stereo-viewing or by viewing the molecule in motion on the console of a computer,” noted Banaszak, who believes combining stereo viewing with the motion capability of computer graphics works best for this. The book, admittedly, was written in 2000 and so much has changed.

These days, thanks to virtual reality, viewing things in 3D has never been easier. That’s why, now more than ever, it’s important for students of biology, chemistry, physics and to use macromolecular structural databases and visualization tools available today — in order to keep up with the changing pace of technology.

Drug Discovery

3D imaging of protein structures is accelerating drug discovery, and are being used alongside genome sequencing, robotics, and bioinformatics. Genome analyses, X-ray analysis, and NMR Spectroscopy, an analytical chemistry technique used in quality control and research for determining the content and purity of a sample, as well as its molecular structure, have identified new protein targets.

A major success in the history of structural biology and drug discovery is thanks to American drug-discovery company Plexxikon’s work on the anti-cancer drug Zelboraf. The drug worked so well in human trials, the trials were stopped so the participants could be given Zelboraf to combat metastatic melanoma, which until then had few treatments.

U.S.-based drug discovery company Plexxikon pioneered a specific image-heavy approach, called Scaffold-Based Drug Discovery™ during the course of designing Zelboraf.

“I think it’s an excellent example of how structural biology helps drug discovery,” says Beamline Scientist James Holton. “It’s nice for me as a structural biologist to see companies like Plexxikon being so successful.”

In an interview, Dr. Peter Reinemer, COO of Proteros, discussed the importance of structural biology.

“Thanks to structural biology, drug developers are now able to have a high-resolved image in atomic resolution of the drug candidate binding the protein target they are studying,” he said.

Structural Biology Today

Nowadays, structural biology is being combined with other techniques in lead identification, such as High Throughput Screening. Through the crystallography of proteins, scientists can now determine structure using an array of data, including structural information, assay data, and biophysical characterization.

News about structural biology highlights insights the discipline has offered into things such as the chemical composition of bone mineral. Molecules created by structural biologists can be found on the RCSB Protein Data Bank, a database of molecular structures. You can even upload the molecules from this database into Virtual Reality software and explore.

Structural Biologists can upload molecules from the RCSB Protein Databank into VR software, like Nanome. Photo courtesy of RCSB PDB.

Structural biologists today discuss technical topics, including the nature of the conformational states of macromolecules and their relative energies, and whether or not these are determined by their environment and ligands, as well as how to map out such properties in detail.

Structural biology has made it clear that proteins are not isolated and act in concert, making protein complexes key for scientists to understand. As our understanding of large assemblies of biomolecules and macromolecular machines increases, structural biology techniques will bring the nanoscale into focus.