Virtual Reality Software For Molecular Modeling and Structure-Based Drug Design

The SARS-CoV-2 virus has forced our global community to practice social distancing and work remotely. This has increased the adoption of cloud-based productivity and collaboration tools and promoted the development of creative new solutions. Scientists have had to find new ways to continue their critical research to study the novel coronavirus and develop drugs. Among these new tools is Nanome, a virtual reality software for molecular modeling and structure-based drug design.

Like all scientists, Dr. Michael Kuiper and his colleagues at CSIRO, an Australian research organization, have had to adapt to the Covid-19 pandemic and find ways to continue their essential work. Dr. Kuiper has been examining the SARS-CoV-2 spike protein in Nanome and recently met with the company’s CEO Steve McCloskey in a virtual workspace. This conversation was recorded and can be viewed on YouTube.      

As a biomolecular modeler, Dr. Kuiper has been collaborating with researchers who monitor the evolution of the SARS-CoV-2 virus and work on vaccine development. During the immersive real-time meeting in Nanome, Dr. Kuiper showed McCloskey his molecular dynamics simulation of the spike protein and highlighted some of the mutations in the UK, South Africa, and Brazil SARS-CoV-2 variants. 

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[3:10] Molecular dynamics simulation of the SARS-CoV-2 spike protein (blue) bound to the human ACE2 receptor (yellow).

Dr. Kuiper loaded his molecular dynamics simulation of the spike protein into the virtual environment, gripped the 3D structure with his virtual hands, and pulled it apart to enlarge it. He pointed out the amino acid lysine Lys484 in the spike protein seen in the South African variant, which mutated from glutamine (E484K mutation). “We see the human receptor ACE2 bind to the spike protein receptor-binding domain, and all of a sudden this mutation starts to make a lot more sense. It’s now creating a salt bridge between the lysine in the spike protein and glutamate in the human ACE2 receptor,” said Dr. Kuiper.

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Caption: [4:35] Dr. Kuiper emphasizes the salt bridge that’s expected to form between the amino acid glutamate Glu75 in the human ACE2 receptor and the amino acid lysine Lys484 in the spike protein, which mutated from glutamine (E484K mutation).

By looking at mutations like the E484K mutation, Dr. Kuiper and his collaborators look for changes in the SARS-CoV-2 virus that may strengthen the interaction and the specificity of its spike protein receptor-binding domain with the human receptor ACE2.
Next, Dr. Kuiper shifted gears away from visualization and modeling of molecular structures to experimental work. He pulled up the journal article “Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding” published in Cell on September 2020.

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[5:40] Dr. Michael Kuiper pulled up the journal article “Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding” published in Cell on September 2020.

In this scientific article, Dr. Kuiper zoomed in on a figure of a heat map in which every small square represents a recombinant protein. Blue colors represent mutations that resulted in tighter ACE2 binding. Red colors represent mutations that resulted in detrimental binding. Dr. Kuiper pointed out position 501 which is blue and cross-referenced it with the table of mutations. This experiment predicted the UK, South Africa, and Brazil lineages, aka B.1.1.7, B.1.351, and P.1.

Infections, immunity, and vaccinations add selection pressure to the SARS-CoV-2 virus, causing it to mutate. This is not necessarily a bad thing, Dr. Kuiper explained, because the virus can also mutate to become less virulent. 

“We’re a giant petri dish right now,” remarked McCloskey.

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[6:56] This figure shows a heat map in which every small square represents a recombinant protein. Blue colors represent mutations that resulted in tighter ACE2 binding. Red colors represent mutations that resulted in detrimental binding.

This experiment also predicted the mink mutation. For an in-depth analysis of this mutation, take a look at the “COVID-19 in VR: Spike Protein Mink Mutations” video. Dr. Kuiper expressed that thanks to high-quality research like this, scientists have already uncovered many valuable insights. However, because there is so much information out there it is difficult to bring it all together.   

“That’s what I love about VR. When you’re sharing that experience with someone it’s no longer just a little blip on a graph. You can actually point at residues. For instance, you can highlight two residues that seem to have an important interaction,” said Dr. Kuiper. 

This model does not take into account solvation effects. (The solvation effect features an interaction between a solute and a solvent, resulting in stabilization of the solute particles in the solution. When an ion in the solution is in the solvated state, it is surrounded or complexed by the molecules of the solvent.) Water molecules affect the interactions between charges and are therefore important for overall interactions. Also, some interactions might be “neutral” and not affect the ACE2 binding but will still make the SARS-CoV-2 virus better at evading our immune systems. Experiments are required to understand how much certain mutations can evade a particular antibody or therapeutic monoclonal antibody. 

Dr. Kuiper has been using Nanome to examine antibody receptor binding by looking at structural information. In virtual reality, he is able to zoom in and look at how the antibody interacts with a particular protein, usually its receptor-binding domain. Changes in residues at the interface are likely to affect the kinetics of the antibody receptor binding. Conducting an initial screen in Nanome helps Dr. Kuiper decide when to proceed to experiments. This is an example of how Nanome helps with drug design decision-making. 

Lastly, Dr. Kuiper played a molecular dynamics simulation and measured the distance between hydrogens at different frames. “Molecular dynamics simulations allow us to highlight some potential interactions which we can then further explore with experiments,” Dr. Kuiper explained. The experimental results will either confirm or refute a particular hypothesis or suggest how to improve a model. 

“Maybe we can suggest other experiments to really get to the bottom of what’s going on in a particular interaction very much like this Cell deep mutational paper that is really a tour de force of experimental work and that can feed directly into our understanding of interactions that are crucial to Covid-19 pandemic,”  Dr. Kuiper said.

Check out  Nanome YouTube channel for more “Covid-19 in VR” episodes and other remote real-time meetings in virtual reality. 

Be sure to check out our webinar “ Advanced Visualization for Healthcare” where the COO and co-founder of Nanome Keita Funakawa will be presenting.

About the Author:

Maria Karpenko

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Maria leads marketing at Nanome, a virtual reality application for molecular modeling and structure-based drug design. Maria has a background in biomedical sciences and over a decade of experience in marketing and communications, digital health research, medical software product design, and editorial direction for an international arts magazine. She is passionate about increasing science and tech literacy and promoting critical thinking. 

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