Hot Topics #27 (June 17, 2024)
FoldFlow-2, BindGPT, compute-optimal pLMs, and deep learning for protein-ligand docking.
Sequence-Augmented SE(3)-Flow Matching For Conditional Protein Backbone Generation: Huguet et al.: May 30, 2024
Abstract: Proteins are essential for almost all biological processes and derive their diverse functions from complex 3D structures, which are in turn determined by their amino acid sequences. In this paper, we exploit the rich biological inductive bias of amino acid sequences and introduce FoldFlow-2, a novel sequence-conditioned SE(3)-equivariant flow matching model for protein structure generation. FoldFlow-2 presents substantial new architectural features over the previous FoldFlow family of models including a protein large language model to encode sequence, a new multi-modal fusion trunk that combines structure and sequence representations, and a geometric transformer based decoder. To increase diversity and novelty of generated samples -- crucial for de-novo drug design -- we train FoldFlow-2 at scale on a new dataset that is an order of magnitude larger than PDB datasets of prior works, containing both known proteins in PDB and high-quality synthetic structures achieved through filtering. We further demonstrate the ability to align FoldFlow-2 to arbitrary rewards, e.g. increasing secondary structures diversity, by introducing a Reinforced Finetuning (ReFT) objective. We empirically observe that FoldFlow-2 outperforms previous state-of-the-art protein structure-based generative models, improving over RFDiffusion in terms of unconditional generation across all metrics including designability, diversity, and novelty across all protein lengths, as well as exhibiting generalization on the task of equilibrium conformation sampling. Finally, we demonstrate that a fine-tuned FoldFlow-2 makes progress on challenging conditional design tasks such as designing scaffolds for the VHH nanobody.
Deep Learning for Protein-Ligand Docking: Are We There Yet?: Morehead et al.: May 23, 2024
Abstract: The effects of ligand binding on protein structures and their in vivo functions carry numerous implications for modern biomedical research and biotechnology development efforts such as drug discovery. Although several deep learning (DL) methods and benchmarks designed for protein-ligand docking have recently been introduced, to date no prior works have systematically studied the behavior of docking methods within the practical context of (1) using predicted (apo) protein structures for docking (e.g., for broad applicability); (2) docking multiple ligands concurrently to a given target protein (e.g., for enzyme design); and (3) having no prior knowledge of binding pockets (e.g., for pocket generalization). To enable a deeper understanding of docking methods' real-world utility, we introduce PoseBench, the first comprehensive benchmark for practical protein-ligand docking. PoseBench enables researchers to rigorously and systematically evaluate DL docking methods for apo-to-holo protein-ligand docking and protein-ligand structure generation using both single and multi-ligand benchmark datasets, the latter of which we introduce for the first time to the DL community. Empirically, using PoseBench, we find that all recent DL docking methods but one fail to generalize to multi-ligand protein targets and also that template-based docking algorithms perform equally well or better for multi-ligand docking as recent single-ligand DL docking methods, suggesting areas of improvement for future work. Code, data, tutorials, and benchmark results are available at this https URL.
Training Compute-Optimal Protein Language Models: Cheng et al.: June 9, 2024
Abstract: We explore optimally training protein language models, an area of significant interest in biological research where guidance on best practices is limited. Most models are trained with extensive compute resources until performance gains plateau, focusing primarily on increasing model sizes rather than optimizing the efficient compute frontier that balances performance and compute budgets. Our investigation is grounded in a massive dataset consisting of 939 million protein sequences. We trained over 300 models ranging from 3.5 million to 10.7 billion parameters on 5 to 200 billion unique tokens, to investigate the relations between model sizes, training token numbers, and objectives. First, we observed the effect of diminishing returns for the Causal Language Model (CLM) and that of overfitting for the Masked Language Model (MLM) when repeating the commonly used Uniref database. To address this, we included metagenomic protein sequences in the training set to increase the diversity and avoid the plateau or overfitting effects. Second, we obtained the scaling laws of CLM and MLM on Transformer, tailored to the specific characteristics of protein sequence data. Third, we observe a transfer scaling phenomenon from CLM to MLM, further demonstrating the effectiveness of transfer through scaling behaviors based on estimated Effectively Transferred Tokens. Finally, to validate our scaling laws, we compare the large-scale versions of ESM-2 and PROGEN2 on downstream tasks, encompassing evaluations of protein generation as well as structure- and function-related tasks, all within less or equivalent pre-training compute budgets
BindGPT: A Scalable Framework for 3D Molecular Design via Language Modeling and Reinforcement Learning: Zhoulus et al.: June 6, 2024
Abstract: Generating novel active molecules for a given protein is an extremely challenging task for generative models that requires an understanding of the complex physical interactions between the molecule and its environment. In this paper, we present a novel generative model, BindGPT which uses a conceptually simple but powerful approach to create 3D molecules within the protein's binding site. Our model produces molecular graphs and conformations jointly, eliminating the need for an extra graph reconstruction step. We pretrain BindGPT on a large-scale dataset and fine-tune it with reinforcement learning using scores from external simulation software. We demonstrate how a single pretrained language model can serve at the same time as a 3D molecular generative model, conformer generator conditioned on the molecular graph, and a pocket-conditioned 3D molecule generator. Notably, the model does not make any representational equivariance assumptions about the domain of generation. We show how such simple conceptual approach combined with pretraining and scaling can perform on par or better than the current best specialized diffusion models, language models, and graph neural networks while being two orders of magnitude cheaper to sample.
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