K. Yi

Kai Yi, Kiarash Jamali, Sjors H. W. Scheres

The recent breakthrough of AlphaFold3 in modeling complex biomolecular interactions, including those between proteins and ligands, nucleotides, or metal ions, creates new opportunities for protein design. In so-called inverse protein folding, the objective is to find a sequence of amino acids that adopts a target protein structure. Many inverse folding methods struggle to predict sequences for complexes that contain non-protein components, and perform poorly with complexes that adopt multiple structural states. To address these challenges, we present ADFLIP (All-atom Discrete FLow matching Inverse Protein folding), a generative model based on discrete flow-matching for designing protein sequences conditioned on all-atom structural contexts. ADFLIP progressively incorporates predicted amino acid side chains as structural context during sequence generation and enables the design of dynamic protein complexes through ensemble sampling across multiple structural states. Furthermore, ADFLIP implements training-free classifier guidance sampling, which allows the incorporation of arbitrary pre-trained models to optimise the designed sequence for desired protein properties. We evaluated the performance of ADFLIP on protein complexes with small-molecule ligands, nucleotides, or metal ions, including dynamic complexes for which structure ensembles were determined by nuclear magnetic resonance (NMR). Our model achieves state-of-the-art performance in single-structure and multi-structure inverse folding tasks, demonstrating excellent potential for all-atom protein design. The code is available at https://github.com/ykiiiiii/ADFLIP.

Hao Chen, Kai Yi, Lin Liu et al.

Causal discovery is a crucial initial step in establishing causality from empirical data and background knowledge. Numerous algorithms have been developed for this purpose. Among them, the score-matching method has demonstrated superior performance across various evaluation metrics, particularly for the commonly encountered Additive Nonlinear Causal Models. However, current score-matching-based algorithms are primarily designed to analyze independent and identically distributed (i.i.d.) data. More importantly, they suffer from high computational complexity due to the pruning step required for handling dense Directed Acyclic Graphs (DAGs). To enhance the scalability of score matching, we have developed a new parent-finding subroutine for leaf nodes in DAGs, significantly accelerating the most time-consuming part of the process: the pruning step. This improvement results in an efficiency-lifted score matching algorithm, termed Parent Identification-based Causal structure learning for both i.i.d. and temporal data on networKs, or PICK. The new score-matching algorithm extends the scope of existing algorithms and can handle static and temporal data on networks with weak network interference. Our proposed algorithm can efficiently cope with increasingly complex datasets that exhibit spatial and temporal dependencies, commonly encountered in academia and industry. The proposed algorithm can accelerate score-matching-based methods while maintaining high accuracy in real-world applications.