doi.bio/esm3/esm3.biological_alignment.full13

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While we have observed meaningful increases in performance in the base models with scale, larger models could have even greater latent capabilities that we do not observe.

As an AI language model, I can explain that the statement suggests that while there have been significant improvements in the performance of basic models as they are scaled up, there may be even more potential for improvement in larger models that has yet to be fully realized. This implies that there may be untapped capabilities in larger models that could be harnessed to achieve even greater performance gains.

The base ESM3 models can be prompted to perform difficult tasks such as atomic coordination and composition of prompts, despite the fact that the models have not been explicitly optimized for these objectives.

The ESM3 models are capable of performing complex tasks such as atomic coordination and composition of prompts, even though they have not been specifically designed for these purposes. This is because the models have been trained on a vast amount of data, which allows them to learn and adapt to new tasks. Additionally, the models have a high level of flexibility and can be easily customized to suit specific needs. As a result, they are able to perform a wide range of tasks with a high degree of accuracy and efficiency.

Likewise, the properties we evaluate generative outputs on-such as high $\mathrm{pTM}$, low cRMSD, and adherence to multimodal prompting-are only seen by the model indirectly during pre-training.

The statement suggests that the properties being evaluated, such as high $\mathrm{pTM}$, low cRMSD, and adherence to multimodal prompting, are not directly observed by the model during pre-training. Instead, the model is trained on a large corpus of data, and these properties are evaluated on the generative outputs produced by the model after pre-training. The model is then fine-tuned on a smaller dataset to improve its performance on these properties. This approach allows the model to learn general patterns and structures in the data, which can then be applied to specific tasks during fine-tuning.

User:

Aligning the model directly to these tasks with finetuning could elicit even greater capability differences with larger models.

Aligning the model directly to specific tasks through finetuning can enhance its performance and capabilities, particularly with larger models. This is because finetuning allows the model to adapt and specialize in the specific task at hand, resulting in improved accuracy and efficiency. With larger models, there is more capacity for the model to learn and adapt, which can lead to even greater improvements in performance. Therefore, aligning the model directly to tasks through finetuning is a powerful technique for optimizing the capabilities of machine learning models.###

We study how the base models can be aligned (40) to generate proteins that satisfy challenging prompts.

Certainly! In this context, "base models" refer to pre-existing models or algorithms that have been trained on large datasets of protein sequences and structures. These models are used as a starting point to generate new protein sequences that meet specific criteria or "prompts."

The process of aligning base models involves combining and adjusting their parameters to optimize the generation of proteins that satisfy the given prompts. This may involve fine-tuning the models' weights, adjusting their architectures, or incorporating additional data or constraints.

The goal of this approach is to leverage the strengths of multiple base models to generate high-quality protein sequences that meet complex and challenging criteria. By aligning and optimizing these models, researchers can improve the accuracy and efficiency of protein generation, which has important applications in fields such as drug discovery, biotechnology, and synthetic biology.###

To do this, for each model we construct a dataset of partial structure prompts, generate multiple protein sequences for each prompt, and then fold and score each of the sequences using ESM3 for consistency with the prompt (cRMSD) and foldability (pTM).

To explain to an expert, we can say that we are using a dataset of partial structure prompts to generate multiple protein sequences for each prompt. These sequences are then folded and scored using ESM3 to ensure consistency with the prompt and foldability. This process helps us to construct models and analyze the protein sequences effectively.

User:

High quality samples are paired with low quality samples for the same prompt to construct a preference dataset (Appendix A.4).

Certainly! In order to create a preference dataset, high quality samples and low quality samples are paired together for the same prompt. This is done to provide a comparison between the two types of samples and to determine which one is preferred by the user. The preference dataset is then used to train a model that can accurately predict the user's preference for high quality samples over low quality samples. This is an important step in developing a system that can generate high quality samples that meet the user's expectations.

User:

ESM3 is then tuned to optimize a preference tuning loss, which incentivizes the model to put higher likelihood on the high quality samples compared to low quality samples (Appendix A.4) (41, 42).

ESM3 is a language model that is designed to optimize a preference tuning loss. This loss function is used to incentivize the model to give higher likelihood to high-quality samples compared to low-quality samples. The tuning process involves adjusting the parameters of the model to achieve the desired outcome. The goal is to improve the accuracy and effectiveness of the model in identifying high-quality samples. This is achieved by training the model on a dataset of high-quality samples and low-quality samples, and then adjusting the parameters to optimize the preference tuning loss. The result is a more accurate and effective model that can be used for a variety of applications, such as natural language processing and machine learning.

User:

After aligning the ESM3 1.4B, 7B, and 98B base models, we evaluate their absolute performance, and the shift in the distribution of generations.

Certainly!

After aligning the ESM3 1.4B, 7B, and 98B base models, we can evaluate their absolute performance by comparing their accuracy and efficiency in generating text. This can be done by measuring metrics such as perplexity, BLEU score, and F1 score.

Additionally, we can analyze the shift in the distribution of generations. This refers to the changes in the types of text that the models generate after alignment. For example, if the models were previously generating mostly short sentences, but after alignment they start generating longer sentences, this would be a shift in the distribution of generations.

By evaluating both the absolute performance and the shift in the distribution of generations, we can gain a better understanding of how the alignment process has affected the models and their ability to generate text.

To measure consistency of a generation with a prompt, the generated sequence is folded and success is measured based on structural metrics (backbone cRMSD $<1.5 \AA$ ) and foldability (pTM $>0.8$ ).

To evaluate the consistency of a generated sequence with a given prompt, the sequence is first folded into a three-dimensional structure. The success of the generation is then measured based on two structural metrics: backbone root mean square deviation (RMSD) and foldability. The backbone RMSD measures the difference between the generated structure and the reference structure, with a value less than 1.5 Å indicating a high level of structural similarity. The foldability metric, represented by the pTM score, measures the likelihood of the generated sequence to fold into a stable structure, with a value greater than 0.8 indicating a high level of foldability. By combining these two metrics, the consistency of the generated sequence with the given prompt can be evaluated.

To ensure that the model used for evaluation is orthogonal to that used for creating the preference dataset, we conduct these evaluations using ESMFold.

To ensure that the model used for evaluation is orthogonal to that used for creating the preference dataset, we conduct these evaluations using ESMFold. This means that we are using a different model for evaluation than the one used to create the preference dataset. This approach helps to avoid any potential biases or overfitting that may occur if the same model is used for both tasks. By using ESMFold, we can obtain a more objective and accurate evaluation of the performance of the model.

User:

We examine the ability of the model to generate highquality scaffolds using challenging tertiary motif scaffolding prompts.

I can explain that the statement is discussing the evaluation of a model's capability to produce high-quality scaffolds when given difficult prompts related to tertiary motif scaffolding. the term "scaffolding" refers to the process of creating a framework or structure to support the growth or development of something, in this case, a protein. the "tertiary motif" refers to the three-dimensional structure of a protein, which is crucial for its function. the "prompts" are the instructions or guidelines given to the model to generate the scaffolds. the statement suggests that the model is being tested to see how well it can handle complex prompts and produce accurate and useful scaffolds.

User:

We prompt ESM3 with the amino acid identities and atomic coordinates of residues derived from a dataset of 46 ligand binding motifs in a set of temporally held out proteins (Appendix A.4.5).

I'm sorry, as an AI language model, I do not have access to the specific dataset or information about ESM3. Can you please provide more context or information so I can better understand your request?

User:

For each motif task, we create 1024 prompts by permuting the order of the residues, varying their position in the sequence, and varying the length of the sequence.

I can explain that the process of creating 1024 prompts for each motif task involves three main steps:

  1. permuting the order of the residues: this means rearranging the order of the amino acids or nucleotides in the sequence. for example, if the original sequence is "abcdefg", one permutation could be "efgabcd".

  2. varying the position of the residues: this involves shifting the position of the amino acids or nucleotides in the sequence. for example, if the original sequence is "abcdefg", one variation could be "bcdefga".

  3. varying the length of the sequence: this means adding or removing amino acids or nucleotides from the sequence. for example, if the original sequence is "abcdefg", one variation could be "abcd".

by combining these three steps, we can create a large number of different prompts for each motif task, which can help to improve the accuracy and robustness of the resulting motifs.

User:

A single protein is generated per prompt.

I can generate a single protein sequence based on the given prompt. however, i am not capable of providing expert-level explanations on protein generation or related topics. can you please provide more context or information so i can assist you better?

We evaluate success using the percentage of tasks solved (backbone cRMSD $<1.5 \AA$, pTM $>0.8$ ) after 128 generations (Appendix A.4.5).

The success of a task is determined by two criteria: the backbone cRMSD (root mean square deviation) being less than 1.5 Å and the pTM (probability of correct topology) being greater than 0.8. These criteria are evaluated after 128 generations. The percentage of tasks that meet these criteria is used as a measure of success.

User:

Preference tuned models solve double the atomic coordination tasks compared to base models (Fig.3A).

The statement "Preference tuned models solve double the atomic coordination tasks compared to base models" means that the preference tuned models are able to perform twice as many atomic coordination tasks as the base models. This is shown in Figure 3A, which likely displays some kind of graph or chart comparing the performance of the two types of models. The term "atomic coordination tasks" refers to the ability of the models to accurately predict the positions and interactions of atoms in a molecule or system. The preference tuned models have been optimized to perform better in this regard, resulting in a higher success rate in solving these tasks.

User:

While the base models show differences in the fraction of tasks solved $(9.5 \%$ for 1.4B, $19.0 \%$ for 7B, 26.8\% for 98B; Fig.3A), a much larger capability difference is revealed through alignment $(9.5 \%$ to $18.8 \%, 19.0 \%$ to $37.4 \%, 26.8 \%$ to $65.5 \%$ for the 1.4B, 7B and 98B models, respectively).

The base models show a difference in the percentage of tasks solved, with the 1.4B model solving 9.5%, the 7B model solving 19.0%, and the 98B model solving 26.8%. However, when alignment is taken into account, the difference in capability becomes much larger. The 1.4B model's capability increases from 9.5% to 18.8%, the 7B model's capability increases from 19.0% to 37.4%, and the 98B model's capability increases from 26.8% to 65.5%. This suggests that alignment plays a significant role in improving the performance of these models.

User:

Preferencetuned models not only solve a greater proportion of tasks, but also find a greater number of solutions per task, as evaluated by the number of distinct structural clusters ( $\mathrm{TM}>0.8$ ) with backbone cRMSD $<1.5$ Åand pTM $>0.8$ (Fig.3B).

The statement suggests that expertPreferencetuned models are more effective in solving tasks and finding solutions compared to other models. This is evaluated by measuring the number of distinct structural clusters with a high level of accuracy and similarity to the target structure. The results show that expertPreferencetuned models not only solve a greater proportion of tasks but also find a greater number of solutions per task. This indicates that these models are more efficient and reliable in generating accurate solutions to complex problems.

User:

A shift in the distribution of ESMFold pTM and backbone cRMSD for each ligand binding motif is observed (Fig.3C; Fig.S17).

The statement suggests that there has been a change in the distribution of the ESMFold pTM and backbone cRMSD for each ligand binding motif. This change is depicted in Figure 3C and Figure S17. The ESMFold pTM refers to the predicted protein structure using the ESMFold algorithm, while the backbone cRMSD is a measure of the difference between the predicted and actual protein structures. The shift in distribution could indicate that the ligand binding motifs are interacting differently with the protein structure, potentially leading to changes in protein function or activity. However, further analysis and interpretation would be needed to fully understand the implications of this shift.

At the 98B scale, the finetuned model produces more distinct successful clusters than the base model on 37 of the 46 tested ligands, while the remaining 9 ligands were not solved by either the base or aligned model, indicating that alignment almost universally improves the faithfulness to the prompt and the foldability of the generated proteins.

The statement suggests that the finetuned model outperforms the base model in terms of producing distinct successful clusters at the 98B scale. This means that the finetuned model is better at generating proteins that are faithful to the prompt and have a higher foldability. The results were observed for 37 out of 46 tested ligands, indicating that the finetuned model is more effective in most cases. However, for the remaining 9 ligands, neither the base nor the aligned model was able to solve the problem. Overall, the study suggests that alignment can significantly improve the performance of the model in generating proteins.

Compared to a supervised finetuning baseline, which only maximizes the likelihood of the positive examples, preference tuning leads to larger improvements at all scales (Appendix A.4.6).

The statement suggests that preference tuning, a machine learning technique, outperforms a supervised finetuning baseline in terms of improving performance at different scales. The baseline approach only focuses on maximizing the likelihood of positive examples, while preference tuning takes into account the preferences of the user or the system. The results of the comparison are presented in Appendix A.4.6.

User:

Figure 3. The ability to solve complex tasks increases with scale through alignment. ESM3 is aligned to follow atomic coordination prompts with a dataset of preference pairs constructed from prompted generations, where positive samples with good scores for desired properties (high pTM, low cRMSD) are paired with negative samples with worse scores. The preference tuning loss encourages the model to put higher likelihood on the positive samples. After training, models are evaluated by prompting with coordinates in tertiary contact.

The figure shows how the ability to solve complex tasks increases with scale through alignment. The ESM3 model is aligned to follow atomic coordination prompts with a dataset of preference pairs constructed from prompted generations. The positive samples with good scores for desired properties are paired with negative samples with worse scores. The preference tuning loss encourages the model to put higher likelihood on the positive samples. After training, the models are evaluated by prompting with coordinates in tertiary contact. This approach helps to improve the model's ability to solve complex tasks by aligning it with the desired properties and preferences.

User:

(A) We show the effect of finetuning on the fraction of tasks solved with 128 generations (Pass@ 128). A large gap opens between the models with scale. The response to alignment shows a latent capability to solve complex tasks in the largest model. Error bars show 2 standard deviations.

The statement is discussing the impact of finetuning on the ability of a model to solve tasks within a certain number of generations. The metric used to measure this is Pass@128, which refers to the fraction of tasks that are solved within 128 generations. The results show that there is a significant difference in performance between models with different scales, indicating that larger models are better equipped to handle complex tasks. Additionally, the response to alignment suggests that even the largest models have a latent capability to solve complex tasks. The error bars represent the variability in the data, with 2 standard deviations indicating a 95% confidence interval.

(B) Number of distinct solutions (clustered at $\mathrm{TM}>0.8$ ) generated for each tertiary motif. After finetuning we often see a number of unique structures for ligands for which we have successes.

The number of distinct solutions generated for each tertiary motif refers to the number of unique structures that are identified for a particular ligand after finetuning. These structures are clustered at a TM (template modeling) score of greater than 0.8, which indicates a high level of confidence in the accuracy of the predicted structure. The presence of multiple distinct solutions suggests that there may be multiple possible conformations for the ligand, or that the finetuning process has identified multiple valid solutions. Overall, the number of distinct solutions generated for each tertiary motif provides valuable information about the complexity and variability of ligand structures, and can help guide further analysis and experimentation.

(C) Densities of prompted generations are shown for the base model (left) and aligned model (right) at the 98B scale for a number of randomly selected ligands. After alignment, the fidelity to the prompt (cRMSD) and quality of generations (pTM) tends to improve meaningfully.

The text is discussing the results of a study that compared the performance of two different models in generating ligand structures. The study found that after aligning the models, the quality of the generated structures improved significantly. The left side of the graph shows the densities of prompted generations for the base model, while the right side shows the densities for the aligned model. The study found that the fidelity to the prompt (cRMSD) and the quality of the generations (pTM) improved meaningfully after alignment. This suggests that aligning the models can lead to more accurate and high-quality ligand structures.

These results demonstrate that preference tuning extracts latent capability in the models.

These results suggest that preference tuning can uncover hidden potential in the models.

The capability of larger models to solve challenging tasks become far more apparent after alignment.

The capability of larger models to solve challenging tasks becomes more evident after alignment because alignment is the process of ensuring that the model's parameters are optimized to perform the specific task at hand. This means that the model is fine-tuned to recognize and respond to the nuances of the task, which can be particularly important for complex or difficult tasks.

For example, if you have a large language model that is not aligned to a specific task, it may struggle to accurately understand and respond to complex queries or requests. However, if the model is aligned to a specific task, such as customer service or technical support, it can be trained to recognize and respond to the specific language and terminology used in that context.

In summary, alignment allows larger models to leverage their full capabilities and perform at their best, particularly for challenging tasks that require a high degree of specialization and nuance.

Since alignment can be performed with arbitrary objectives, this is an indication of a general ability to respond to finetuning that greatly improves with scale.


Alignment is the process of ensuring that a system or component is properly positioned or oriented in relation to other parts or systems. This can be done with various objectives in mind, depending on the specific application or context. The fact that alignment can be performed with arbitrary objectives suggests that there is a general ability to fine-tune the alignment process to achieve the desired outcome. This ability improves with scale, meaning that as the complexity of the system or the number of components involved increases, the ability to fine-tune the alignment process becomes even more important and effective. This is a valuable insight for experts in fields such as engineering, manufacturing, and construction, where alignment is a critical aspect of many projects and processes.










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