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Designing drug molecules is no longer just about generation, but control. NEC Laboratories America introduces MolDiffdAE, a diffusion-based framework that enables precise, multi-objective tuning of 3D molecular properties. By learning a semantic space, researchers can efficiently guide design, accelerating drug discovery and exploration of chemical space.
Controlled generation of 3D molecules is highly valuable in drug design, enabling targeted modifications that preserve core structure and binding-relevant geometry while improving developability-related properties. While equivariant diffusion models achieve state-of-the-art de novo 3D molecule generation, reliably controlling multiple molecular properties remains challenging. A key limitation is structural: diffusion models typically lack an explicit latent space for targeted manipulation. We propose a semantics-guided equivariant autoencoding diffusion model that learns a disentangled semantic embedding of 3D molecules via an auxiliary encoder, to achieve fine-grained control over the generative denoising process. This semantic embedding enables efficient retrieval, random generation and controlled generation. By directly manipulating the embedding, we effectively steer the molecular generation toward desired compositions, shapes and physicochemical properties, and further enhance the generation quality with retrieval-augmented generation (RAG) using the embedding as the query. Importantly, the disentangled embedding offers significant advantages for joint manipulation of multiple properties. Experiments demonstrate precise and data-efficient property control while preserving non-targeted properties.
In protein biophysics, the separation between the functionally important residues (forming the active site or binding surface) and those that create the overall structure (the fold) is a well-established and fundamental concept. Identifying and modifying those functional sites is critical for protein engineering but computationally nontrivial, and requires significant domain knowledge. To automate this process from a data-driven perspective, we propose a disentangled Wasserstein autoencoder with an auxiliary classifier, which isolates the function-related patterns from the rest with theoretical guarantees. This enables one-pass protein sequence editing and improves the understanding of the resulting sequences and editing actionsinvolved. To demonstrate its effectiveness, we apply it to T-cell receptors (TCRs), a well-studied structure-function case. We show that our method can be used to alterthe function of TCRs without changing the structural backbone, outperforming several competing methods in generation quality and efficiency, and requiring only 10% of the running time needed by baseline models. To our knowledge, this is the first approach that utilizes disentangled representations for TCR engineering.
T cells monitor the health status of cells by identifying foreign peptides displayed on their surface. T-cell receptors (TCRs), which are protein complexes found on the surface of T cells, are able to bind to these peptides. This process is known as TCR recognition and constitutes a key step for immune response. Optimizing TCR sequences for TCR recognition represents a fundamental step towards the development of personalized treatments to trigger immune responses killing cancerous or virus-infected cells. In this paper, we formulated the search for these optimized TCRs as a reinforcement learning (RL) problem and presented a framework TCRPPO with a mutation policy using proximal policy optimization. TCRPPO mutates TCRs into effective ones that can recognize given peptides. TCRPPO leverages a reward function that combines the likelihoods of mutated sequences being valid TCRs measured by a new scoring function based on deep autoencoders, with the probabilities of mutated sequences recognizing peptides from a peptide-TCR interaction predictor. We compared TCRPPO with multiple baseline methods and demonstrated that TCRPPO significantly outperforms all the baseline methods to generate positive binding and valid TCRs. These results demonstrate the potential of TCRPPO for both precision immunotherapy and peptide-recognizing TCR motif discovery.
Motivation: MHC Class I protein plays an important role in immunotherapy by presenting immunogenic peptides to anti-tumor immune cells. The repertoires of peptides for various MHC Class I proteins are distinct, which can be reflected by their diverse binding motifs. To characterize binding motifs for MHC Class I proteins, in vitro experiments have been conducted to screen peptides with high binding affinities to hundreds of given MHC Class I proteins. However, considering tens of thousands of known MHC Class I proteins, conducting in vitro experiments for extensive MHC proteins is infeasible, and thus a more efficient and scalable way to characterize binding motifs is needed.Results: We presented a de novo generation framework, coined PepPPO, to characterize binding motif for any given MHC Class I proteins via generating repertoires of peptides presented by them. PepPPO leverages a reinforcement learning agent with a mutation policy to mutate random input peptides into positive presented ones. Using PepPPO, we characterized binding motifs for around 10 000 known human MHC Class I proteins with and without experimental for the rapid screening of neoantigens at a much lower time cost than previous deep-learning methods.
Traditional embedding approaches associate a real-valued embedding vector with each symbol or data point, which is equivalent to applying a linear transformation to “one-hot” encoding of discrete symbols or data objects. Despite simplicity, these methods generate storage-inefficient representations and fail to effectively encode the internal semantic structure of data, especially when the number of symbols or data points and the dimensionality of the real-valued embedding vectors are large. In this paper, we propose a regularized autoencoder framework to learn compact Hierarchical K-way D-dimensional (HKD) discrete embedding of symbols or data points, aiming at capturing essential semantic structures of data. Experimental results on synthetic and real-world datasets show that our proposed HKD embedding can effectively reveal the semantic structure of data via hierarchical data visualization and greatly reduce the search space of nearest neighbor retrieval while preserving high accuracy.
Parametric embedding methods such as parametric t-distributed Stochastic Neighbor Embedding (pt-SNE) enables out-of-sample data visualization without further computationally expensive optimization or approximation. However, pt-SNE favors small mini-batches to train a deep neural network but large mini-batches to approximate its cost function involving all pairwise data point comparisons, and thus has difficulty in finding a balance. To resolve the conflicts, we present parametric t-distributed stochastic exemplar-centered embedding. Our strategy learns embedding parameters by comparing training data only with precomputed exemplars to indirectly preserve local neighborhoods, resulting in a cost function with significantly reduced computational and memory complexity. Moreover, we propose a shallow embedding network with high-order feature interactions for data visualization, which is much easier to tune but produces comparable performance in contrast to a deep feedforward neural network employed by pt-SNE. We empirically demonstrate, using several benchmark datasets, that our proposed method significantly outperforms pt-SNE in terms of robustness, visual effects, and quantitative evaluations.