Proteins are the foundation of all life we currently know. With their virtually limitless diversity, they can perform a broad variety of biological functions, from delivering oxygen to cells and acting as chemical messengers to defending the body against pathogens. Furthermore, most biochemical reactions are only possible thanks to enzymes, a special type of protein catalysts.
The molecular surface of proteins is the key to their function, such as docking small molecules or other proteins or driving chemical reactions. Much like a key fits only one lock and activates it, proteins often interact exclusively with a single molecular structure that precisely matches their surface.
This principle is exploited in drug development: drug molecules are designed to bind to specific proteins, altering their surface and, consequently, their behavior. The newly created “neo-surface” can in turn form novel interactions with other proteins. Molecules designed to bring together different proteins that otherwise would not interact are called “molecular glues,” and are a promising modality to treat diseases by inactivating or degrading proteins that cause disease.
Proteins are the foundation of all life we currently know. With their virtually limitless diversity, they can perform a broad variety of biological functions, from delivering oxygen to cells and acting as chemical messengers to defending the body against pathogens. Furthermore, most biochemical reactions are only possible thanks to enzymes, a special type of protein catalysts.
The molecular surface of proteins is the key to their function, such as docking small molecules or other proteins or driving chemical reactions. Much like a key fits only one lock and activates it, proteins often interact exclusively with a single molecular structure that precisely matches their surface.
This principle is exploited in drug development: drug molecules are designed to bind to specific proteins, altering their surface and, consequently, their behavior. The newly created “neo-surface” can in turn form novel interactions with other proteins. Molecules designed to bring together different proteins that otherwise would not interact are called “molecular glues,” and are a promising modality to treat diseases by inactivating or degrading proteins that cause disease.
New proteins with a molecular fingerprint
A long-term collaboration of Michael Bronstein, scientific director of AITHYRA, the new Institute of the Austrian Academy of Sciences (ÖAW), with the team of Bruno Correia at the EPFL Laboratory for Immunoengineering and Protein Design has pioneered the use of geometric deep learning architecture called “Molecular Surface Interaction Fingerprinting” (MaSIF) to design new proteins with desired molecular surface properties.
In the latest study published in Nature this week, the team applied MaSIF to proteins with bound drug molecules and showed that it can be used to design proteins that bind to these neo-surfaces.
“One of the key challenges of machine learning approaches is their generalization ability, or how well the method works on data never seen before,” explains Bronstein. “One of the surprising and satisfying outcomes of our study is that a neural network trained on natural interactions between proteins generalizes very well to protein-ligand neo-surfaces never seen before. It seems that geometric descriptors of molecular surfaces extracted by our method are a sort of “universal language” for protein interactions.”
“The new approach allows us to design switchable protein interactions,” Correia says. “We can create new protein binders that interact with target proteins only in the presence of a small molecule. This opens a new avenue to precise dosing and control of biological drugs such as those used in oncological immunotherapies.”
Experiments validate virtual results
The researchers experimentally validated their novel protein binders against three drug-bound protein complexes containing the hormone progesterone, the FDA-approved leukemia drug Venetoclax, and the naturally occurring antibiotic Actinonin, respectively. The protein binders designed using MaSIF successfully recognized each drug-protein complex with high affinity.
The team explains that this was possible because MaSIF is based on general surface features that apply to proteins and small molecules alike, so they were able to map the small molecule features onto the same descriptor space that MaSIF was trained on for proteins.
“MaSIF has a relatively small number of parameters—around 70,000 versus billions for large deep learning systems like ChatGPT,” explains Ph.D. student and co-author Arne Schneuing, “This is possible because we use only key surface features, resulting in a high level of abstraction. In other words, we don’t give the system the full picture; only the part we think matters for solving the problem.”
Experiments validate virtual results
The researchers experimentally validated their novel protein binders against three drug-bound protein complexes containing the hormone progesterone, the FDA-approved leukemia drug Venetoclax, and the naturally occurring antibiotic Actinonin, respectively. The protein binders designed using MaSIF successfully recognized each drug-protein complex with high affinity.
The team explains that this was possible because MaSIF is based on general surface features that apply to proteins and small molecules alike, so they were able to map the small molecule features onto the same descriptor space that MaSIF was trained on for proteins.
“MaSIF has a relatively small number of parameters—around 70,000 versus billions for large deep learning systems like ChatGPT,” explains Ph.D. student and co-author Arne Schneuing, “This is possible because we use only key surface features, resulting in a high level of abstraction. In other words, we don’t give the system the full picture; only the part we think matters for solving the problem.”
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