Speaker unverified: belief

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…some people still think it should be a lot nicer and they’re, and they’re right. And they’re right. But yeah, I think it was, you know, at the time, maybe a little bit easier than, than other things. The other thing part, I think led to, to the community and to some extent, I think, you know, like the somewhat the trust in the community. Kind of what we, what we put out is the fact that, you know, it’s not really been kind of, you know, one model, but, and maybe we’ll talk about it, you know, after Boltz 1, you know, there were maybe another couple of models kind of released, you know, or open source kind of soon after. We kind of continued kind of that open source journey or at least Boltz 2, where we are not only improving kind of structure prediction, but also starting to do affinity predictions, understanding kind of the strength of the interactions between these different models, which is this critical component. critical property that you often want to optimize in discovery programs. And then, you know, more recently also kind of protein design model. And so we’ve sort of been building this suite of, of models that come together, interact with one another, where, you know, kind of, there is almost an expectation that, you know, we, we take very at heart of, you know, always having kind of, you know, across kind of the entire suite of different tasks, the best or across the best. model out there so that it’s sort of like our open source tool can be kind of the go-to model for everybody in the, in the industry. I really want to talk about Boltz 2, but before that, one last question in this direction, was there anything about the community which surprised you? Were there any, like, someone was doing something and you’re like, why would you do that? That’s crazy. Or that’s actually genius. And I never would have thought about that. I mean, we’ve had many contributions. I think like some of the. Interesting ones, like, I mean, we had, you know, this one individual who like wrote like a complex GPU kernel, you know, for part of the architecture on a piece of, the funny thing is like that piece of the architecture had been there since AlphaFold 2, and I don’t know why it took Boltz for this, you know, for this person to, you know, to decide to do it, but that was like a really great contribution. We’ve had a bunch of others, like, you know, people figuring out like ways to, you know, hack the model to do something. They click peptides, like, you know, there’s, I don’t know if there’s any other interesting ones come to mind. ke, you know, people figuring out like ways to, you know, hack the model to do something. They click peptides, like, you know, there’s, I don’t know if there’s any other interesting ones come to mind. One cool one, and this was, you know, something that initially was proposed as, you know, as a message in the Slack channel by Tim O’Donnell was basically, he was, you know, there are some cases, especially, for example, we discussed, you know, antibody-antigen interactions where the models don’t necessarily kind of get the right answer. What he noticed is that, you know, the models were somewhat stuck into predicting kind of the antibodies. And so he basically ran the experiments in this model, you can condition, basically, you can give hints. And so he basically gave, you know, random hints to the model, basically, okay, you should bind to this residue, you should bind to the first residue, or you should bind to the 11th residue, or you should bind to the 21st residue, you know, basically every 10 residues scanning the entire antigen. Residues are the... The amino acids. The amino acids, yeah. So the first amino acids. The 11 amino acids, and so on. So it’s sort of like doing a scan, and then, you know, conditioning the model to predict all of them, and then looking at the confidence of the model in each of those cases and taking the top. And so it’s sort of like a very somewhat crude way of doing kind of inference time search. But surprisingly, you know, for antibody-antigen prediction, it actually kind of helped quite a bit. And so there’s some, you know, interesting ideas that, you know, obviously, as kind of developing the model, you say kind of, you know, wow. This is why would the model, you know, be so dumb. But, you know, it’s very interesting. And that, you know, leads you to also kind of, you know, start thinking about, okay, how do I, can I do this, you know, not with this brute force, but, you know, in a smarter way. And so we’ve also done a lot of work on that direction. And that speaks to, like, the, you know, the power of scoring. We’re seeing that a lot. I’m sure we’ll talk about it more when we talk about BullsGen. But, you know, our ability to, like, take a structure and determine that that structure is, like... Good. You know, like, somewhat accurate. Whether that’s a single chain or, like, an interaction is a really powerful way of improving, you know, the models. Like, sort of like, you know, if you can sample a ton and you assume that, like, you know, if you sample enough, you’re likely to have, like, you know, the good structure. Then it really just becomes a ranking problem. And, you know, now we’re, you know, part of the inference time scaling that Gabby was talking about is very much that. It’s like, you know, the more we sample, the more we, like, you know, the ranking model. The ranking model ends up finding something it really likes. And so I think our ability to get better at ranking, I think, is also what’s going to enable sort of the next, you know, next big, big breakthroughs. Interesting. up finding something it really likes. And so I think our ability to get better at ranking, I think, is also what’s going to enable sort of the next, you know, next big, big breakthroughs. Interesting. But I guess there’s a, my understanding, there’s a diffusion model and you generate some stuff and then you, I guess, it’s just what you said, right? Then you rank it using a score and then you finally... And so, like, can you talk about those different parts? Yeah. So, first of all, like, the... One of the critical kind of, you know, beliefs that we had, you know, also when we started working on Boltz 1 was sort of like the structure prediction models are somewhat, you know, our field version of some foundation models, you know, learning about kind of how proteins and other molecules interact. And then we can leverage that learning to do all sorts of other things. And so with Boltz 2, we leverage that learning to do affinity predictions. So understanding kind of, you know, if I give you this protein, this molecule. How tightly is that interaction? For Boltz 1, what we did was taking kind of that kind of foundation models and then fine tune it to predict kind of entire new proteins. And so the way basically that that works is sort of like instead of for the protein that you’re designing, instead of fitting in an actual sequence, you fit in a set of blank tokens. And you train the models to, you know, predict both the structure of kind of that protein. The structure also, what the different amino acids of that proteins are. And so basically the way that Boltz 1 operates is that you feed a target protein that you may want to kind of bind to or, you know, another DNA, RNA. And then you feed the high level kind of design specification of, you know, what you want your new protein to be. For example, it could be like an antibody with a particular framework. It could be a peptide. It could be many other things. And that’s with natural language or? And that’s, you know, basically, you know, prompting. And we have kind of this sort of like spec that you specify. And, you know, you feed kind of this spec to the model. And then the model translates this into, you know, a set of, you know, tokens, a set of conditioning to the model, a set of, you know, blank tokens. And then, you know, basically the codes as part of the diffusion models, the codes. It’s a new structure and a new sequence for your protein. And, you know, basically, then we take that. And as Jeremy was saying, we are trying to score it and, you know, how good of a binder it is to that original target. You’re using basically Boltz to predict the folding and the affinity to that molecule. So and then that kind of gives you a score? Exactly.…

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