Proteins are the basic building blocks of life and its very foundation. Studying proteins opens a door for us to explore and understand the secrets of human life and health.

The 8^th Chinese Protein Society Symposium was held in the Yunqi Town International Convention and Exhibition Center from Nov. 24 to 26, 2023. It is the highest-level protein science conference in China, attracting 1,082 participants.

Over 40 presentations were delivered during the eight sessions, covering topics such as methods in protein science, proteins and diseases, enzymes and sensors, protein folding and design, chemical biology, proteins and cells, nucleic acids and proteins, membrane proteins, and supermolecular machines.

The following is a brief summary of some of the presentations at the symposium.

Protein Folding

Proteins were first described by the Dutch chemist Gerardus Johannes Mulder in 1838. Over the past 200 years, we have learned a great deal about their structure, nature, and composition, but there is still far more to explore.

In 1953, in the journal Nature, James Watson and Francis Crick published their discovery of the double helix structure of DNA, taking the study of life science into the era of ATCG coding. Based on this seminal work, Crick came up with the concept of "central dogma", which encapsulated the idea that once information was transferred from nucleic acids (DNA and RNA) and encoded in proteins, it could not revert back to nucleic acids.

If we consider DNA as a code book, RNA is the key phrase that is constantly repeated. Three RNA bases constitute a single code—an amino acid—which “translates” a series of polypeptides. Polypeptides are then connected and folded into proteins with 3D structures. Folded amino acid sequences go on to assemble themselves into protein complexes.

There are only 20 naturally occurring amino acids in the human body, but from these, an incredibly complex life form is created. Proteins are like paper; they can be folded into planes, cylinders, or tiles. Their shape determines their function.

But this folding presents major challenges to scientists.

The particle diameter of proteins is about 1–100 nanometers, while the wavelength of visible light is more than 390 nanometers. This means that trying to observe proteins with visible light causes diffraction because proteins are smaller than the wavelength of light. At first, scientists tried to crystalize proteins and analyze the structures of proteins using irradiation, but that proved difficult. With the invention of cryo-EM, observation no longer requires crystallization. Over time, we have also created tools such as molecular markers and mass spectrometry analysis that enable us to recognize and analyze proteins.

In 2021, the Jianping Wu Laboratory at Westlake University deciphered CatSper, which controls sperm activation, and discovered previously unknown protein components. This research has laid solid groundwork for the development of drugs to treat infertility and achieve non-hormonal contraception.

Protein Machines

To a great extent, the structure of a protein after it has been folded determines its function. However, the study of protein structures is not a goal in itself. The goal is to understand and cure diseases that affect life quality.

If we think of life as a machine, then proteins are the most crucial components. Multiple proteins together constitute protein machines, which become parts of larger structures in the body, such as the muscles and bones that support the body and control its movement. Transmembrane transport proteins are indispensable in managing vital activities—regulating and catalyzing enzyme complexes to build the antibodies that play a vital role in our immune defense system.

Another example is membrane protein receptor complexes. These are groups of molecules on cell surfaces that recognize and combine with biologically active materials. After they bind with ligands, the complexes send out signals that activate and initiate downstream physical and chemical changes—they are key “gears” in driving cell activity. GPCR is the largest group of membrane proteins in eukaryotes and is a primary target for drug development. Studying GPCR structures provides vital information to support the development of treatments for neural and immune system diseases as well as cancer.

Prof. Huaqiang Xu

Prof. Huaqiang Xu from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences presented his research on G-protein-coupled receptors (GPCRs). He previously worked as a researcher at GSK plc and as director of the drug development center at the Van Andel Institute. Focusing on the complexities of GPCR signaling, he showed how small-molecule ligands combine into the "pockets" of GPCR cells in unique ways and how manipulating this characteristic facilitates the design of medicines to meet different treatment needs.

His studies are opening up new directions for drug research and development. Understanding the combination of small-molecule drugs and protein “pockets” could help minimize the side effects of drugs.

Although they have enormous potential, GPCRs are still understudied. Further research is needed to reveal their working mechanisms, which could offer new perspectives on the treatment of disease. Prof. Jinpeng Sun from Shandong University also shared his work on GPCR ligand detection, signal transmission, and functions. Sun’s team discovered a series of key GPCR ligands, shedding light on around 20 crucial GPCRs. His presentation on GPCRs as receivers for sound and their effect on balance was particularly well-received.

Prof. Xiaoliang Xie

Prof. Xiaoliang Xie, an academician and director of the Changping Laboratory, was one of the founding fathers of single-molecule enzymology and single-molecule biophysics. He shared his work on COVID-19. At the beginning of the pandemic, he and his colleagues started searching for neutralizing antibodies using single-molecule sequencing. By studying the key amino acids in the COVID-19 virus, they predicted how mutations could occur that might allow the virus to evade the human immune system. Their predictions were highly consistent with how the virus actually mutated. Xie firmly believes that the lessons learned will allow scientists to swiftly identify possible antibodies when the next pandemic strikes.

Protein Creation

Aside from being crucial components of our living “machine”, the study of proteins also provides a window into life itself that allows us to gain insights into how life works. As our understanding develops, we are progressing from deciphering protein codes to actually coding new proteins. Prof. David Baker, director of the Institute for Protein Design at the University of Washington, gave the presentation Design of New Protein Functions Using Deep Learning, which drew attention to the potential for designing new protein features.

Protein design involves the creation of proteins with brand new structures and functions without the need to use existing natural proteins. Specifically designed new proteins might be better able to meet our needs and are considered a major leap forward in science.

David Baker

AlphaFold is the ChatGPT of protein design—an AI system that analyzes the 3D structure of proteins. By 2020, scientists had obtained the 3D spatial structure of nearly 200,000 large-molecule proteins. With the help of AI, nearly 700 million protein structures have been predicted, expanding our knowledge exponentially.

However, AlphaFold feeds on the protein structures produced by scientists. Currently, it can only predict single protein structures and cannot predict the structural changes that occur after proteins combine with DNA or small molecules. However, AI is still an effective tool in our exploration of protein structures.

With the help of AI, Baker and his team have enabled proteins to fold into predetermined 3D structures and acquire certain functions by coding the amino acid sequence in each protein. They have used deep learning to develop a series of tools for this purpose and have achieved impressive results in drug development, polypeptide design, and new material design.

To increase the effectiveness of antibody drugs for COVID-19, Baker’s team designed a conjugated protein that wraps around the three spike sites on the surface of COVID-19. Deep learning tools have also achieved impressive results in work on polypeptides and disordered proteins that lack fixed structures. Baker’s lab has designed a conjugated protein that achieves full suppression of the beta-amyloid peptide that plays a crucial role in the progression of Alzheimer’s disease.

Similar work is carried out at Westlake. In 2020, Prof. Peilong Lu’s lab designed the first de novo precision-designed transmembrane protein. Lu’s work could be used to develop new detection methods for biotechnology, such as nanopore gene sequencing and molecular detection. Lu formerly worked as a postdoc in Baker’s lab.

According to Lu, the work of his laboratory is to create proteins that have never existed. “It is estimated that the number of proteins that appear in nature is around 10 to the power of 12, but so far we’ve only tested 1,400-fold types among all these proteins. It’s fair to deduce that the proteins that are found in nature are only a fraction of what is possible. After all, over billions of years, even nature has not been able to create every protein that could possibly exist.”

If nature can only achieve this after billions of years, then mankind could be facing a galaxy of potential proteins. What exists now is just a glimpse of what is possible as we find our way forward into the future. This is a journey that is just beginning.