Dmitry Korkin on the Modular Evolution of Proteins, SARS-CoV-2 Viral Structure, and Computational Biology

This episode features Dmitry Korkin, a professor of bioinformatics and computational biology, discussing the intricate world of proteins and viruses. The conversation begins by challenging the simplistic view of proteins as basic building blocks, instead highlighting protein domains as the fundamental functional and evolutionary units due to their modular complexity. This modularity, where proteins are seen as 'strings of beads' made of domains, provides a hierarchical understanding of protein organization and function, a concept often overlooked in popular discourse but crucial for understanding biological processes. The discussion emphasizes how breakthroughs in techniques like cryo-electron microscopy have enabled scientists to resolve the complex 3D structures of larger molecules, revealing this underlying modularity.

A significant portion of the conversation delves into the SARS-CoV-2 virus, particularly the spike (S) protein. Korkin explains its structure as a homotrimer, detailing the asynchronous opening of its receptor-binding domains (RBDs) to attach to human ACE2 receptors. He also elaborates on other structural proteins—the E (envelope), M (membrane), and N (nucleocapsid) proteins—and their roles in forming the viral particle, including the M protein's ability to form a stable lattice. A key distinction is made regarding the evolutionary stability of these proteins, with the M protein identified as a potentially more stable and thus promising target for drug development compared to the rapidly mutating spike protein.

From a practical standpoint, understanding these complex viral structures and their evolutionary dynamics is presented as indispensable for designing effective vaccines and treatments. Korkin discusses potential strategies, such as developing nanoparticles that mimic the virus to block ACE2 receptors or targeting the M protein to disrupt the viral envelope. He stresses the importance of studying viral evolution to anticipate mutations, predict resistance to vaccines and treatments, and forecast future viral trajectories. The concept of alternative splicing is introduced as another layer of complexity, where a single gene can produce multiple protein products dynamically in response to disease or developmental stages, further illustrating the sophisticated regulatory mechanisms in biology.

Broader implications include the dual nature of viruses as both terrifying threats to civilization and beautiful sources of insight into the nature of life, potentially even extraterrestrial life. The 'ongoing expansion of the protein universe' is framed through the lens of modularity, with protein domains and flexible 'linkers' evolving under different selective pressures. The conversation also draws parallels between biological self-replication and concepts in computer science, such as 'quines' and 'code golf,' underscoring the universal principles of self-organization and efficiency. Ultimately, the discussion highlights the continuous 'arms race' between human intervention (vaccination) and viral evolution, emphasizing the critical role of deep biological understanding in this ongoing challenge.

proteins are actually a more much more complicated so they have so-called modular complexity

the protein domain is the basic building block of the function that we think about proteins doing

the first experimental structure of a sars cove to protein was the cribium structure of the s protein so the spike protein

the primary function is to get attached to the you know h2 receptor human receptor

there was a recent mutation that... showed that actually because of these mutations you have more than one arms opening up

understanding all of this is really useful for trying to figure out like developing a vaccine or some kind of drug to attack any aspects of this

if you are able to destroy the outer shell you are essentially destroying the the the viral particle itself

this protein is evolutionary more stable compared to the say to the spike protein

mutations are sort of a general way for these viruses to evolve

one of the critical directions in understanding the virus is to uh to understand its evolution in order to uh sort of understand the mechanisms the key mechanisms that lead the virus to jump

if if i were to pick a single keyword about uh protein evolution i would pick modularity

the gene is not it's no longer equal to one protein it actually can uh produce multiple functionally uh you know active protein products