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Focus Area: Drug Discovery

MicrobioRaman: an open-access web repository for microbiological Raman spectroscopy data

Here we present the establishment of an open-access web-based repository for microbiological Raman spectroscopy data. The data collection, called ‘MicrobioRaman’ (, was inspired by the great success and usefulness of research databases such as GenBank and UniProt. This centralized repository, residing within the BioStudies database — which is maintained by a public institution, the European Bioinformatics Institute — minimizes the risk of data loss or eventual abandonment, offering a long-term common reference for analysis with advantages in accessibility and transparency over commercial data analysis tools. We feel that MicrobioRaman will provide a foundation for this growing field by serving as an open-access repository for sharing microbiological Raman data and through the codification of a set of reporting standards. Contributors: Kang Soo Lee, Zachary Landry, Awais Athar, Uria Alcolombri, Pratchaya Pramoj Na Ayutthaya, David Berry, Philippe de Bettignies, Ji-Xin Cheng, Gabor Csucs, Li Cui, Volker Deckert, Thomas Dieing, Jennifer Dionne, Ondrej Doskocil, Glen D’Souza, Cristina García-Timermans, Notburga Gierlinger, Keisuke Goda, Roland Hatzenpichler, Richard Henshaw, Wei Huang, Ievgeniia Iermak, Natalia Ivleva, Janina Kneipp, Patrick Kubryk, Kirsten Küsel, Tae Kwon Lee, Sung Sik Lee, Bo Ma, Clara Martínez-Pérez, Pavel Matousek, Rainer U. Meckenstock, Wei Min, Peter Mojzeš, Oliver Müller, Naresh Kumar, Per Halkjær Nielsen, Ioan Notingher, Márton Palatinszky, Fátima C. Pereira, Giuseppe Pezzotti, Zdenek Pilat, Filip Plesinger, Jürgen Popp, Alexander Probst, Alessandra Riva, Amr. Saleh, Ota Samek, Haley Sapers, Olga Schubert, Astrid Stubbusch, Gordon Taylor, Michael Wagner, Jing Wang, Huabing Yin, Yang Yue, Renato Zenobi, Jacopo Zini, Ugis Sarkans & Roman Stocker. Learn more

DisCo-Diff: Enhancing Continuous Diffusion Models with Discrete Latents

Diffusion models (DMs) have revolutionized generative learning. They utilize a diffusion process to encode data into a simple Gaussian distribution. However, encoding a complex, potentially multimodal data distribution into a single continuous Gaussian distribution arguably represents an unnecessarily challenging learning problem. We propose Discrete-Continuous Latent Variable Diffusion Models (DisCo-Diff) to simplify this task by introducing complementary discrete latent variables. We augment DMs with learnable discrete latents, inferred with an encoder, and train DM and encoder end-to-end. DisCo-Diff does not rely on pre-trained networks, making the framework universally applicable. The discrete latents significantly simplify learning the DM's complex noise-to-data mapping by reducing the curvature of the DM's generative ODE. An additional autoregressive transformer models the distribution of the discrete latents, a simple step because DisCo-Diff requires only few discrete variables with small codebooks. We validate DisCo-Diff on toy data, several image synthesis tasks as well as molecular docking, and find that introducing discrete latents consistently improves model performance. For example, DisCo-Diff achieves state-of-the-art FID scores on class-conditioned ImageNet-64/128 datasets with ODE sampler.

Contributors: Yilun Xu, Gabriele Corso, Arash Vahdat, Karsten Kreis Learn more

Causal Discovery with Fewer Conditional Independence Tests

Many questions in science center around the fundamental problem of understanding causal relationships. However, most constraint-based causal discovery algorithms, including the well-celebrated PC algorithm, often incur an exponential number of conditional independence (CI) tests, posing limitations in various applications. Addressing this, our work focuses on characterizing what can be learned about the underlying causal graph with a reduced number of CI tests. We show that it is possible to a learn a coarser representation of the hidden causal graph with a polynomial number of tests. This coarser representation, named Causal Consistent Partition Graph (CCPG), comprises of a partition of the vertices and a directed graph defined over its components. CCPG satisfies consistency of orientations and additional constraints which favor finer partitions. Furthermore, it reduces to the underlying causal graph when the causal graph is identifiable. As a consequence, our results offer the first efficient algorithm for recovering the true causal graph with a polynomial number of tests, in special cases where the causal graph is fully identifiable through observational data and potentially additional interventions.

Contributors: Kirankumar Shiragur, Jiaqi Zhang Learn more

Harmonic Self-Conditioned Flow Matching for joint Multi-Ligand Docking and Binding Site Design

A significant amount of protein function requires binding small molecules, including enzymatic catalysis. As such, designing binding pockets for small molecules has several impactful applications ranging from drug synthesis to energy storage. Towards this goal, we first develop HarmonicFlow, an improved generative process over 3D protein-ligand binding structures based on our self-conditioned flow matching objective. FlowSite extends this flow model to jointly generate a protein pocket's discrete residue types and the molecule's binding 3D structure. We show that HarmonicFlow improves upon state-of-the-art generative processes for docking in simplicity, generality, and average sample quality in pocket-level docking. Enabled by this structure modeling, FlowSite designs binding sites substantially better than baseline approaches.

: Hannes Stark, Bowen Jing Learn more

CLIPZyme: Reaction-Conditioned Virtual Screening of Enzymes

Computational screening of naturally occurring proteins has the potential to identify efficient catalysts among the hundreds of millions of sequences that remain uncharacterized. Current experimental methods remain time, cost and labor intensive, limiting the number of enzymes they can reasonably screen. In this work, we propose a computational framework for in-silico enzyme screening. Through a contrastive objective, we train CLIPZyme to encode and align representations of enzyme structures and reaction pairs. With no standard computational baseline, we compare CLIPZyme to existing EC (enzyme commission) predictors applied to virtual enzyme screening and show improved performance in scenarios where limited information on the reaction is available (BEDROC of 44.69%). Additionally, we evaluate combining EC predictors with CLIPZyme and show its generalization capacity on both unseen reactions and protein clusters.

Contributor: Itamar Chinn Learn more

Generative Flows on Discrete State-Spaces: Enabling Multimodal Flows with Applications to Protein Co-Design”

Combining discrete and continuous data is an important capability for generative models. We present Discrete Flow Models (DFMs), a new flow-based model of discrete data that provides the missing link in enabling flow-based generative models to be applied to multimodal continuous and discrete data problems. Our key insight is that the discrete equivalent of continuous space flow matching can be realized using Continuous Time Markov Chains. DFMs benefit from a simple derivation that includes discrete diffusion models as a specific instance while allowing improved performance over existing diffusion-based approaches. We utilize our DFMs method to build a multimodal flow-based modeling framework. We apply this capability to the task of protein co-design, wherein we learn a model for jointly generating protein structure and sequence. Our approach achieves state-of-the-art co-design performance while allowing the same multimodal model to be used for flexible generation of the sequence or structure.

Contributors: Andrew Campbell, Jason Yim, Tom Rainforth Learn more

Improving protein optimization with smoothed fitness landscapes

The ability to engineer novel proteins with higher fitness for a desired property would be revolutionary for biotechnology and medicine. Modeling the combinatorially large space of sequences is infeasible; prior methods often constrain optimization to a small mutational radius, but this drastically limits the design space. Instead of heuristics, we propose smoothing the fitness landscape to facilitate protein optimization. First, we formulate protein fitness as a graph signal then use Tikunov regularization to smooth the fitness landscape. We find optimizing in this smoothed landscape leads to improved performance across multiple methods in the GFP and AAV benchmarks. Second, we achieve state-of-the-art results utilizing discrete energy-based models and MCMC in the smoothed landscape. Our method, called Gibbs sampling with Graph-based Smoothing (GGS), demonstrates a unique ability to achieve 2.5 fold fitness improvement (with in-silico evaluation) over its training set. GGS demonstrates potential to optimize proteins in the limited data regime. Code:

Contributors: Andrew Kirjner, Jason Yim, Raman Samusevich, Shahar Bracha, Ila Fiete Learn more

Deep Confident Steps to New Pockets: Strategies for Docking Generalization

Accurate blind docking has the potential to lead to new biological breakthroughs, but for this promise to be realized, docking methods must generalize well across the proteome. Existing benchmarks, however, fail to rigorously assess generalizability. Therefore, we develop DOCKGEN, a new benchmark based on the ligand binding domains of proteins, and we show that existing machine learning-based docking models have very weak generalization abilities. We carefully analyze the scaling laws of ML-based docking and show that, by scaling data and model size, as well as integrating synthetic data strategies, we are able to significantly increase the generalization capacity and set new state-of-the-art performance across benchmarks. Further, we propose CONFIDENCE BOOTSTRAPPING, a new training paradigm that solely relies on the interaction between diffusion and confidence models and exploits the multi-resolution generation process of diffusion models. We demonstrate that CONFIDENCE BOOTSTRAPPING significantly improves the ability of ML-based docking methods to dock to unseen protein classes, edging closer to accurate and generalizable blind docking methods.

Contributors Gabriele Corso, Arthur Deng, Benjamin Fry, Nicholas Polizzi Learn more

Machine learning for antimicrobial peptide identification and design

Artificial intelligence (AI) and machine learning (ML) models are being deployed in many domains of society and have recently reached the field of drug discovery. Given the increasing prevalence of antimicrobial resistance, as well as the challenges intrinsic to antibiotic development, there is an urgent need to accelerate the design of new antimicrobial therapies. Antimicrobial peptides (AMPs) are therapeutic agents for treating bacterial infections, but their translation into the clinic has been slow owing to toxicity, poor stability, limited cellular penetration and high cost, among other issues. Recent advances in AI and ML have led to breakthroughs in our abilities to predict biomolecular properties and structures and to generate new molecules. The ML-based modelling of peptides may overcome some of the disadvantages associated with traditional drug discovery and aid the rapid development and translation of AMPs. Here, we provide an introduction to this emerging field and survey ML approaches that can be used to address issues currently hindering AMP development. We also outline important limitations that can be addressed for the broader adoption of AMPs in clinical practice, as well as new opportunities in data-driven peptide design.

Contributors: Fangping Wan, Felix Wong, Cesar de la Fuente-Nunez Learn more

Dirichlet Flow Matching with Applications to DNA Sequence Design

Discrete diffusion or flow models could enable faster and more controllable sequence generation than autoregressive models. We show that naïve linear flow matching on the simplex is insufficient toward this goal since it suffers from discontinuities in the training target and further pathologies. To overcome this, we develop Dirichlet flow matching on the simplex based on mixtures of Dirichlet distributions as probability paths. In this framework, we derive a connection between the mixtures' scores and the flow's vector field that allows for classifier and classifier-free guidance. Further, we provide distilled Dirichlet flow matching, which enables one-step sequence generation with minimal performance hits, resulting in O(L) speedups compared to autoregressive models. On complex DNA sequence generation tasks, we demonstrate superior performance compared to all baselines in distributional metrics and in achieving desired design targets for generated sequences. Finally, we show that our classifier-free guidance approach improves unconditional generation and is effective for generating DNA that satisfies design targets. Code is available here:

Contributors: Hannes Stark, Bowen Jing, Chenyu Wang, Gabriele Corso, Bonnie Berger Learn more
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