The Science Behind the Image Contest Winners: Group II Intron Ribozyme

The BPS Art of Science Image Contest took place again this year, during the 61st Annual Meeting in New Orleans. The winning image was submitted by Giulia Palermo, a postdoctoral fellow in the group of J. Andrew McCammon at the University of California, San Diego. A team of three scientists composed the image:  Giulia Palermo created the original design, Amelia Palermo (ETH, Zurich) made the handmade painting, and Lorenzo Casalino (SISSA, Trieste) performed digital manipulation on the picture. Giulia Palermo took some time to provide information about the image and the science it represents.

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With this picture we would like to send as the main message that Physics and Art try to interpret the beauty of Nature in different ways but there is a natural overlap between these disciplines, which could lead to wonderful discoveries and amazing beauty.

Group II intron ribozyme perform self-splicing reactions. In the picture, two scissors are used to represent this mechanism. What we like about this image is how a handmade painting could capture the fundamental aspects of the mechanistic action of the system. Besides the beauty of handmade painting, we enjoyed our teamwork and, fostered by the passion for this research, we have been motivated to submit this image to the Art of Science Image Contest.

This image has been inspired by the work we have done in the group of Prof. Alessandra Magistrato (SISSA, Trieste), in collaboration with Prof. Ursula Rothlisberger (EPFL), which resulted in the publication of our research in the Journal of American Chemical Society and in the Journal of Chemical Theory and Computation, while other equally exciting results are in preparation for publication. Below, we report details of our publications:

  1. Casalino, G. Palermo, U. Rothlisberger and A. Magistrato. Who Activates the Nucleophile in Ribozyme Catalysis? An Answer from the Splicing Mechanism of Group II Introns. J. Am. Chem. Soc. 2016, 138, 1034.
  1. Casalino, G. Palermo, N. Abdurakhmonova, U. Rothlisberger and A. Magistrato. Development of Site-specific Mg-RNA Force Field Parameters: A Dream or Reality? Guidelines from Combined Molecular Dynamics and Quantum Mechanics Simulations. J. Chem. Theory Comput. 2017, 13, 340–352.

My research exploits advanced computational methods – based on classical and quantum molecular dynamics (MD), novel cryo-electron microscopy (cryo-EM) refinement – and their integration with experiments to unravel the function and improve biological applications of key protein/nucleic acids complexes directly responsible for gene regulation, with important therapeutic applications for cancer treatment and genetic diseases. As a next-generation computational biophysicist, I aim at going beyond the current limits of time scale and system size of biomolecular simulations, unraveling the function of increasingly realistic biological systems of extreme biological importance, contributing in their applications for effective translational research.

The World Health Organization reported that ~8.2 million citizens die each year for cancer, while genetic diseases affect millions of people. As such, the clarification of the fundamental mechanisms responsible of gene expression and of their therapeutic implications is of key urgency to society.  By using advanced computational methods and by their integration with experiments, I seek to unravel the function and improve applications of biological systems of extreme importance. My current interest – as a post-doc in McCammon’s lab at UCSD – is in the clarification of the mechanistic function of the CRISPR-Cas9 system via computational methods. Additionally, I am interested in long non-coding RNA, which regulates gene expression, and in intriguing protein/DNA systems, whose mechanistic function is at the basis of genetic inheritance.

Cholesterol: More Than Just Heart Attacks

When most people hear the word “cholesterol,” they think about their diet, heart disease, and statins. In fact, cholesterol is also an essential component in the membranes of your cells, the biosynthesis of which evolved in reBPJ_109_5.c1.inddsponse to the appearance on earth of an oxygen rich atmosphere, roughly two and a half billion years ago.

So what does cholesterol do for your cell membranes? It has been known for many years that cholesterol organizes and orders the fatty acid component of the membrane, leading to a thicker and more tightly packed lipid bilayer. This makes the membrane more effective as a barrier against ions, water, and other small molecules. However, the biophysical details responsible for this behavior have remained largely unknown.

The cover image shows a configuration sampled by a molecular dynamics simulation of a mixture of two lipids and cholesterol, modeled in all-atom detail. The hydrocarbon chains are rendered in red (a sphingolipid) or blue (a monounsaturated phospholipid). Cholesterol is rendered in yellow.  The shapes of the lipids reflect the details of local packing and order. In the more yellow and red region (cholesterol and sphingolipid rich), the chains of the sphingolipid tend to pack tightly into local hexagonal arrays. Though locally hexagonal, this phase is still fluid, and hence referred to as “liquid-ordered.” In the more blue region (richer in unsaturated chains), the lipids are more loosely packed, and are rendered as Voronoi polygons. The corners of the polygons are smoothed by Bezier splines to evoke the softness of the more fluid, “liquid-disordered” phase. The heights of the polygonal solids are the relative heights of the lipids, revealing that the thickening effect of cholesterol is very local. The image was rendered using the Tachyon ray tracing software.

More simulations like this are sure to follow, with ever more complex lipid mixtures. With high-precision models and careful simulation protocols, these efforts will reveal how compositionally complex membrane mixtures conspire to organize for functional ends, such as signaling and trafficking. Whatever is revealed, it is clear that cholesterol will play a leading role.

—Edward Lyman, Alexander Sodt, Richard Pastor

Molecular Dynamics Analysis of Antibody Recognition and Escape by Human H1N1 Influenza Hemagglutinin

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How did you compose this image?

The cover art–composed of the 1918 antibody (Ig-2D1) binding to the 2009 hemagglutinin (09HA)–is generated from visual molecular dynamics and enhanced in GIMP (GNU image manipulation program). The protein at the bottom is the 09HA, colored by residue name, and the protein on top is the antibody, colored in grey. The protein system was solvated in a water box and simulated in NAMD. We aimed to study the interactions between the antibody and antigen under simulated physiological conditions. We were inspired by the idea that inside the body, everything is dark, but the antibody and antigen complex is our “super star” and our study of interest; we let it “glow” in the dark as a symbol of human understanding of the mechanism of the interactions. The protein complexes are typically surrounded by water molecules, signified by the bubbles or water droplets. The bubbles reflect the complex and echoes the advances in knowledge and celebration of science.

How does this image reflect your scientific research?

The human immune response to the influenza virus is a fascinating area of research, and the thrust of our research aims to provide detailed molecular-level understanding of the mechanism of interactions between antibodies and antigens through computational simulation. In this particular study, we have, to our knowledge, uncovered novel understandings of how mutations in the influenza HA protein, in particular, the 2009 pandemic H1N1 HA, may confer immune escape from human defense. In particular, water molecules may contribute to weakening the interactions between antibodies and antigens in conjunction with the mutations.

Can you please provide a few real-world examples of your research?

Computational simulation plays a key role in advancing our understanding of human-pathogen interaction, and molecular dynamics simulations have been our main tool of investigation into various aspects of the influenza virus. For example, these techniques have been applied in the design of new inhibitors against influenza neuraminidase, and the current study explores the use of molecular dynamic simulation to compare antibody binding affinities, and could have immediate impact on antibody design and engineering.

How does your research apply to those who are not working in your specific field?

Atomic-level physics-based simulations are accurate enough to provide predictive hypotheses for experimental validation. The techniques are now applicable to researchers studying protein-protein and protein-small molecule interactions in other fields. Continued advances in computing technology will continue to enhance the realism of the modeled experimental systems, driving our “computational microscope” toward better understanding of natural phenomena and ultimately leading to better and safer therapeutics for humans.

Do you have a website where our readers can view your recent research?

https://amarolab.ucsd.edu

http://nbcr.ucsd.edu

http://www.sdsc.edu

– Pek Ieong, Rommie E. Amaro, Wilfred W. Li