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A. Zambon

Publications and source records attributed to A. Zambon.

2 recordsLinked to original sources

Sampling at intermediate temperatures is optimal for training large language models in protein structure prediction

Using a statistical mechanics framework, we investigate the parameter space of transformer models trained on protein sequence data. We sample the loss landscape at varying temperatures using Langevin dynamics to characterize the low-loss manifold, and to understand the mechanisms underlying transformers' superior performance in protein structure prediction. We find that, at variance with networks not based on the attention mechanism, the lack of a first--order--like transition in the loss of the transformer produces a range of intermediate temperatures with good learning properties; this is true both for synthetic and natural protein sequences. We also show that the parameters of most layers are highly conserved at these temperatures if the dimension of the embedding is optimal, and we provide an operative way to find this dimension. Additionally, we show that the attention matrix is more predictive of the contact maps of the protein at higher temperatures and for higher dimensions of the embedding than those optimal for learning. Finally, we showed that the models sampled at intermediate temperatures can predict the free-energy variation upon mutation, better than models obtained through standard optimization techniques.

cond-mat.dis-nn↗

Structure of the space of folding protein sequences defined by large language models

Proteins populate a manifold in the high-dimensional sequence space whose geometrical structure guides their natural evolution. Leveraging recently-developed structure prediction tools based on transformer models, we first examine the protein sequence landscape as defined by the folding score function. This landscape shares characteristics with optimization challenges encountered in machine learning and constraint satisfaction problems. Our analysis reveals that natural proteins predominantly reside in wide, flat minima within this energy landscape. To investigate further, we employ statistical mechanics algorithms specifically designed to explore regions with high local entropy in relatively flat landscapes. Our findings indicate that these specialized algorithms can identify valleys with higher entropy compared to those found using traditional methods such as Monte Carlo Markov Chains. In a proof-of-concept case, we find that these highly entropic minima exhibit significant similarities to natural sequences, especially in critical key sites and local entropy. Additionally, evaluations through Molecular Dynamics suggests that the stability of these sequences closely resembles that of natural proteins. Our tool combines advancements in machine learning and statistical physics, providing new insights into the exploration of sequence landscapes where wide, flat minima coexist alongside a majority of narrower minima.

q-bio.BM↗