doi.bio/esm3/esm3.discussion.full14

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We have found that language models can reach a design space of proteins that is distant from the space explored by natural evolution, and generate functional proteins that would take evolution hundreds of millions of years to discover.

As an AI language model, I can explain that the statement suggests that language models have the ability to explore a wider range of protein designs compared to natural evolution. This means that language models can generate functional proteins that may not have been discovered by natural evolution for a very long time. This could potentially lead to the development of new and innovative protein-based technologies and solutions.

User:

Protein language models do not explicitly work within the physical constraints of evolution, but instead can implicitly construct a model of the multitude of potential paths evolution could have followed.

Protein language models are computational models that are used to predict the structure and function of proteins. These models are based on the principles of evolutionary biology, but they do not explicitly consider the physical constraints of evolution. Instead, they implicitly construct a model of the many possible paths that evolution could have taken to produce the observed protein structures and functions.

In other words, protein language models use statistical and computational methods to analyze large amounts of data on protein sequences and structures, and then use this information to make predictions about the properties of new proteins. While these models are based on the principles of evolution, they do not explicitly model the physical constraints that shape the evolution of proteins.

Instead, protein language models rely on the assumption that the observed protein structures and functions are the result of a complex interplay between evolutionary history, physical constraints, and functional requirements. By analyzing large amounts of data on protein sequences and structures, these models can implicitly capture the many possible paths that evolution could have taken to produce the observed proteins.

Overall, protein language models are a powerful tool for predicting the structure and function of proteins, and they can provide valuable insights into the evolutionary history of these important molecules. However, it is important to remember that these models are based on statistical and computational methods, and they do not explicitly model the physical constraints of evolution.

Proteins can be seen as existing within an organized space where each protein is neighbored by every other that is one mutational event away (54).

This statement suggests that proteins can be visualized as occupying a structured space where each protein is surrounded by other proteins that are only one mutation away from it. This implies that there is a high degree of interconnectedness and proximity between different proteins in this space. This concept is important in understanding the relationships between different proteins and how they may interact with each other. It also highlights the potential for small changes in protein structure to have significant effects on their function and interactions.

User:

The structure of evolution appears as a network within this space, connecting all proteins by the paths that evolution can take between them.

The statement suggests that the process of evolution can be visualized as a network within a certain space, where each protein is connected to other proteins through the possible paths that evolution can take between them. This implies that the evolution of one protein is not independent of the evolution of other proteins, and that the relationships between proteins can be represented as a complex network. This network can be analyzed to understand the patterns and mechanisms of protein evolution, and to identify key proteins or pathways that are important for the evolution of a particular organism or group of organisms. The statement is likely intended for an expert in the field of evolutionary biology or bioinformatics, who would be familiar with the concepts and tools used to study protein evolution and network analysis.

The paths that evolution can follow are the ones by which each protein transforms into the next without the collective loss of function of the system it is a part of.

This statement refers to the concept of protein evolution, which is the process by which proteins change over time through genetic mutations and natural selection. The idea is that the evolution of proteins is constrained by the need for the protein to maintain its function within the larger biological system it is a part of. In other words, the changes that occur in a protein's sequence must not disrupt the overall function of the system it is involved in. This is because proteins often interact with other proteins and molecules in complex networks, and any disruption to one protein can have cascading effects on the entire system. Therefore, the paths that evolution can follow are limited to those that allow for the gradual transformation of a protein without causing a loss of function in the larger system. This concept is important for understanding how proteins evolve and how they contribute to the overall function of biological systems.

It is in this space that a language model sees proteins.

I'm sorry, but the given statement "It is in this space that a language model sees proteins" does not make sense and lacks context. Can you please provide more information or clarify the statement so I can assist you better?

It sees the data of proteins as filling this space, densely in some regions, and sparsely in others, revealing the parts that are accessible to evolution.

This statement suggests that the data of proteins is being analyzed in terms of its spatial distribution, with some regions being highly populated with data and others being relatively sparse. This analysis is being used to identify areas of the protein that are more likely to undergo evolutionary changes, as these regions are more accessible to the forces of natural selection. Essentially, the idea is that by understanding the spatial distribution of protein data, we can gain insights into how these proteins are likely to evolve over time.

Since the next token is generated by evolution, it follows that to solve the training task of predicting the next token, a language model must predict how evolution moves through the space of possible proteins.

As an AI language model, I can explain that the statement suggests that predicting the next token in a sequence of amino acids requires understanding how evolution shapes the sequence of amino acids in proteins. This is because the next token in the sequence is determined by the process of evolution, which involves mutations and natural selection. Therefore, to accurately predict the next token, a language model must be able to simulate the process of evolution and predict how it will shape the sequence of amino acids in proteins. This requires a deep understanding of the principles of evolution and the complex interactions between amino acids in proteins.

User:

To do so it will need to learn what determines whether a path is feasible for evolution.

To explain this to an expert, we need to understand the concept of path feasibility in the context of evolution. Path feasibility refers to the likelihood of a particular evolutionary path being taken by a species or population. This is determined by various factors such as genetic variation, environmental pressures, and the availability of resources.

For example, if a population has limited genetic variation, it may not be able to evolve in response to changing environmental conditions. Similarly, if a species is unable to access the necessary resources to survive and reproduce, it may not be able to evolve to adapt to new conditions.

To determine whether a path is feasible for evolution, scientists may use various methods such as genetic analysis, experimental studies, and computer simulations. By understanding the factors that influence path feasibility, researchers can better predict how species and populations will evolve in response to changing conditions.

Overall, the concept of path feasibility is crucial for understanding the mechanisms of evolution and predicting how species will respond to environmental changes.

Simulations are computational representations of reality.

Simulations are computer-based models that mimic real-world systems or processes. They are used to study complex phenomena, test theories, and make predictions about future events. Simulations can range from simple mathematical models to complex, multi-dimensional representations of physical systems. They are often used in fields such as engineering, physics, economics, and biology to gain insights into complex systems that would be difficult or impossible to study through direct observation or experimentation. By allowing researchers to manipulate variables and observe the outcomes, simulations can help to identify patterns, test hypotheses, and make predictions about real-world phenomena.###

In that sense a language model which can predict possible outcomes of evolution can be said to be a simulator of it.

I can explain that a language model that can predict possible outcomes of evolution can be considered a simulator of it because it is capable of mimicking the process of evolution and generating potential outcomes based on certain parameters and variables. this type of language model can be used to study and understand the mechanisms of evolution, as well as to make predictions about future evolutionary trends and patterns. by simulating the process of evolution, researchers can gain insights into how species adapt and change over time, and how environmental factors can influence the course of evolution. overall, a language model that can simulate evolution can be a valuable tool for scientists and researchers in the field of evolutionary biology.

ESM3 is an emergent simulator that has been learned from solving a token prediction task on data generated by evolution.

ESM3 is a type of simulator that has been developed using an emergent approach. This means that the simulator has been designed to learn and adapt based on the data it receives. In this case, the data used to train the simulator was generated by an evolutionary process.

The simulator was specifically trained to solve a token prediction task, which involves predicting the next token in a sequence of data. This task is commonly used in natural language processing and other machine learning applications.

Overall, ESM3 is a powerful tool for simulating complex systems and predicting future outcomes based on historical data. Its ability to learn and adapt makes it a valuable resource for experts in a variety of fields.###

It has been theorized that neural networks discover the underlying structure of the data they are trained to predict $(55,56)$.

Neural networks are a type of machine learning algorithm that are designed to recognize patterns in data. They are modeled after the structure and function of the human brain, with interconnected nodes that process and transmit information.

When a neural network is trained on a dataset, it adjusts its internal parameters in order to minimize the difference between its predicted outputs and the actual outputs in the training data. This process is known as backpropagation.

As the neural network continues to learn from the data, it begins to discover the underlying structure and relationships within the data. This is because the network is able to identify patterns and correlations that may not be immediately apparent to a human observer.

For example, if a neural network is trained to recognize handwritten digits, it may discover that certain features, such as the presence of loops or the orientation of lines, are important for distinguishing between different digits. By learning these underlying structures, the neural network is able to make more accurate predictions on new, unseen data.

In summary, neural networks are able to discover the underlying structure of the data they are trained on by adjusting their internal parameters to minimize the difference between predicted and actual outputs, and by identifying patterns and correlations within the data.

In this way, solving the token prediction task would require the model to learn the deep structure that determines which steps evolution can take, i.e.

In order to solve the token prediction task, the model must be able to understand the underlying structure that governs the evolution of the system. This means that the model must be able to identify the specific steps that can be taken in the evolution process, and predict which tokens will be produced as a result of these steps. Essentially, the model must be able to learn the rules that govern the evolution of the system, and use this knowledge to make accurate predictions about future outcomes. This requires a deep understanding of the system and its underlying structure, and the ability to identify patterns and relationships that may not be immediately apparent.

User:

the fundamental biology of proteins.

Proteins are complex biomolecules that play a crucial role in the structure and function of living organisms. They are made up of long chains of amino acids, which are linked together by peptide bonds. The sequence of amino acids in a protein determines its unique three-dimensional structure, which in turn determines its function.

Proteins have a wide range of functions in the body, including catalyzing chemical reactions, transporting molecules across cell membranes, providing structural support, and regulating gene expression. Enzymes, for example, are proteins that catalyze specific chemical reactions in the body. Hemoglobin, on the other hand, is a protein that transports oxygen in the blood.

The process of protein synthesis begins with the transcription of DNA into messenger RNA (mRNA), which is then translated into a sequence of amino acids by ribosomes. The sequence of amino acids in a protein is determined by the genetic code, which specifies the order of nucleotides in the mRNA.

Once a protein has been synthesized, it may undergo post-translational modifications, such as folding, cleavage, or the addition of chemical groups. These modifications can further alter the protein's structure and function.

In summary, proteins are essential biomolecules that play a critical role in the structure and function of living organisms. Their unique three-dimensional structures are determined by the sequence of amino acids, which is encoded in the genetic code.

In ESM3's generation of a new fluorescent protein, it is the first chain of thought to B8 that is the most intriguing.

I'm sorry, but as an AI language model, I do not have access to the specific context or information regarding ESM3's generation of a new fluorescent protein and the chain of thought to B8. Can you please provide more details or context so I can better understand and assist you?

At 96 mutations to B8's closest neighbor there are $\binom{229}{96} \times 19^{96}$ possible proteins, an astronomical number out of which only a vanishingly small fraction can have function, since fluorescence falls off sharply even after just a few random mutations.

The statement is discussing the number of possible proteins that can be created through mutations of a specific protein, B8. The number of possible proteins is calculated using the binomial coefficient, which represents the number of ways to choose a certain number of items from a larger set. In this case, the binomial coefficient is used to calculate the number of ways to choose 96 mutations from a set of 229 possible mutations.

The resulting number is then multiplied by the number of possible amino acids that can be substituted at each of the 96 mutation sites, which is 19 (the number of naturally occurring amino acids). This gives the total number of possible proteins that can be created through mutations of B8.

However, the statement also notes that only a very small fraction of these possible proteins are likely to have any function, as even small changes to a protein can significantly alter its properties. This means that while there may be a large number of possible proteins, only a few of them are likely to be useful or have any biological significance.

The existence of $\mathrm{C} 10$ and other bright designs in the neighborhood of B8 confirms that in the first chain of thought to B8, ESM3 found a new part of the space of proteins that, although unexplored by nature, is dense with fluorescent proteins.

The discovery of C10 and other bright designs near B8 suggests that ESM3 has identified a previously unexplored region of protein space that is rich in fluorescent proteins. This finding supports the idea that there are many undiscovered fluorescent proteins in nature, and that ESM3 is a useful tool for identifying them.