Alex Morehead

Alex Morehead, Jianlin Cheng

Denoising diffusion probabilistic models (DDPMs) have pioneered new state-of-the-art results in disciplines such as computer vision and computational biology for diverse tasks ranging from text-guided image generation to structure-guided protein design. Along this latter line of research, methods have recently been proposed for generating 3D molecules using equivariant graph neural networks (GNNs) within a DDPM framework. However, such methods are unable to learn important geometric properties of 3D molecules, as they adopt molecule-agnostic and non-geometric GNNs as their 3D graph denoising networks, which notably hinders their ability to generate valid large 3D molecules. In this work, we address these gaps by introducing the Geometry-Complete Diffusion Model (GCDM) for 3D molecule generation, which outperforms existing 3D molecular diffusion models by significant margins across conditional and unconditional settings for the QM9 dataset and the larger GEOM-Drugs dataset, respectively, and generates more novel and unique unconditional 3D molecules for the QM9 dataset compared to previous methods. Importantly, we demonstrate that the geometry-complete denoising process of GCDM learned for 3D molecule generation enables the model to generate a significant proportion of valid and energetically-stable large molecules at the scale of GEOM-Drugs, whereas previous methods fail to do so with the features they learn. Additionally, we show that extensions of GCDM can not only effectively design 3D molecules for specific protein pockets but also that GCDM's geometric features can be repurposed to consistently optimize the geometry and chemical composition of existing 3D molecules for molecular stability and property specificity, demonstrating new versatility of molecular diffusion models. Our source code and data are freely available at https://github.com/BioinfoMachineLearning/Bio-Diffusion.

Alex Morehead, Jianlin Cheng

The field of geometric deep learning has had a profound impact on the development of innovative and powerful graph neural network architectures. Disciplines such as computer vision and computational biology have benefited significantly from such methodological advances, which has led to breakthroughs in scientific domains such as protein structure prediction and design. In this work, we introduce GCPNet, a new geometry-complete, SE(3)-equivariant graph neural network designed for 3D molecular graph representation learning. Rigorous experiments across four distinct geometric tasks demonstrate that GCPNet's predictions (1) for protein-ligand binding affinity achieve a statistically significant correlation of 0.608, more than 5% greater than current state-of-the-art methods; (2) for protein structure ranking achieve statistically significant target-local and dataset-global correlations of 0.616 and 0.871, respectively; (3) for Newtownian many-body systems modeling achieve a task-averaged mean squared error less than 0.01, more than 15% better than current methods; and (4) for molecular chirality recognition achieve a state-of-the-art prediction accuracy of 98.7%, better than any other machine learning method to date. The source code, data, and instructions to train new models or reproduce our results are freely available at https://github.com/BioinfoMachineLearning/GCPNet.

Elham Soltanikazemi, Raj S. Roy, Farhan Quadir et al.

Predicted inter-chain residue-residue contacts can be used to build the quaternary structure of protein complexes from scratch. However, only a small number of methods have been developed to reconstruct protein quaternary structures using predicted inter-chain contacts. Here, we present an agent-based self-learning method based on deep reinforcement learning (DRLComplex) to build protein complex structures using inter-chain contacts as distance constraints. We rigorously tested DRLComplex on two standard datasets of homodimeric and heterodimeric protein complexes (i.e., the CASP-CAPRI homodimer and Std_32 heterodimer datasets) using both true and predicted interchain contacts as inputs. Utilizing true contacts as input, DRLComplex achieved high average TM-scores of 0.9895 and 0.9881 and a low average interface RMSD (I_RMSD) of 0.2197 and 0.92 on the two datasets, respectively. When predicted contacts are used, the method achieves TM-scores of 0.73 and 0.76 for homodimers and heterodimers, respectively. Our experiments find that the accuracy of reconstructed quaternary structures depends on the accuracy of the contact predictions. Compared to other optimization methods for reconstructing quaternary structures from inter-chain contacts, DRLComplex performs similar to an advanced gradient descent method and better than a Markov Chain Monte Carlo simulation method and a simulated annealing-based method, validating the effectiveness of DRLComplex for quaternary reconstruction of protein complexes.

Xiao Chen, Alex Morehead, Jian Liu et al.

Proteins interact to form complexes to carry out essential biological functions. Computational methods have been developed to predict the structures of protein complexes. However, an important challenge in protein complex structure prediction is to estimate the quality of predicted protein complex structures without any knowledge of the corresponding native structures. Such estimations can then be used to select high-quality predicted complex structures to facilitate biomedical research such as protein function analysis and drug discovery. We challenge this significant task with DProQ, which introduces a gated neighborhood-modulating Graph Transformer (GGT) designed to predict the quality of 3D protein complex structures. Notably, we incorporate node and edge gates within a novel Graph Transformer framework to control information flow during graph message passing. We train and evaluate DProQ on four newly-developed datasets that we make publicly available in this work. Our rigorous experiments demonstrate that DProQ achieves state-of-the-art performance in ranking protein complex structures.

Alex Morehead, Xiao Chen, Tianqi Wu et al.

Protein complexes are macromolecules essential to the functioning and well-being of all living organisms. As the structure of a protein complex, in particular its region of interaction between multiple protein subunits (i.e., chains), has a notable influence on the biological function of the complex, computational methods that can quickly and effectively be used to refine and assess the quality of a protein complex's 3D structure can directly be used within a drug discovery pipeline to accelerate the development of new therapeutics and improve the efficacy of future vaccines. In this work, we introduce the Equivariant Graph Refiner (EGR), a novel E(3)-equivariant graph neural network (GNN) for multi-task structure refinement and assessment of protein complexes. Our experiments on new, diverse protein complex datasets, all of which we make publicly available in this work, demonstrate the state-of-the-art effectiveness of EGR for atomistic refinement and assessment of protein complexes and outline directions for future work in the field. In doing so, we establish a baseline for future studies in macromolecular refinement and structure analysis.

Alex Morehead, Nabin Giri, Jian Liu et al.

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 the latest docking and structure prediction methods within the broadly applicable context of (1) using predicted (apo) protein structures for docking (e.g., for applicability to new proteins); (2) binding multiple (cofactor) ligands concurrently to a given target protein (e.g., for enzyme design); and (3) having no prior knowledge of binding pockets (e.g., for generalization to unknown pockets). To enable a deeper understanding of docking methods' real-world utility, we introduce PoseBench, the first comprehensive benchmark for broadly applicable protein-ligand docking. PoseBench enables researchers to rigorously and systematically evaluate DL methods for apo-to-holo protein-ligand docking and protein-ligand structure prediction using both primary ligand 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 (1) DL co-folding methods generally outperform comparable conventional and DL docking baseline algorithms, yet popular methods such as AlphaFold 3 are still challenged by prediction targets with novel binding poses; (2) certain DL co-folding methods are highly sensitive to their input multiple sequence alignments, while others are not; and (3) DL methods struggle to strike a balance between structural accuracy and chemical specificity when predicting novel or multi-ligand protein targets. Code, data, tutorials, and benchmark results are available at https://github.com/BioinfoMachineLearning/PoseBench.

Maged Shoman, Armstrong Aboah, Alex Morehead et al.

Automating the product checkout process at conventional retail stores is a task poised to have large impacts on society generally speaking. Towards this end, reliable deep learning models that enable automated product counting for fast customer checkout can make this goal a reality. In this work, we propose a novel, region-based deep learning approach to automate product counting using a customized YOLOv5 object detection pipeline and the DeepSORT algorithm. Our results on challenging, real-world test videos demonstrate that our method can generalize its predictions to a sufficient level of accuracy and with a fast enough runtime to warrant deployment to real-world commercial settings. Our proposed method won 4th place in the 2022 AI City Challenge, Track 4, with an F1 score of 0.4400 on experimental validation data.

Alex Morehead, Watchanan Chantapakul, Jianlin Cheng

Semi-supervised learning (SSL) has recently received increased attention from machine learning researchers. By enabling effective propagation of known labels in graph-based deep learning (GDL) algorithms, SSL is poised to become an increasingly used technique in GDL in the coming years. However, there are currently few explorations in the graph-based SSL literature on exploiting classical dimensionality reduction techniques for improved label propagation. In this work, we investigate the use of dimensionality reduction techniques such as PCA, t-SNE, and UMAP to see their effect on the performance of graph neural networks (GNNs) designed for semi-supervised propagation of node labels. Our study makes use of benchmark semi-supervised GDL datasets such as the Cora and Citeseer datasets to allow meaningful comparisons of the representations learned by each algorithm when paired with a dimensionality reduction technique. Our comprehensive benchmarks and clustering visualizations quantitatively and qualitatively demonstrate that, under certain conditions, employing a priori and a posteriori dimensionality reduction to GNN inputs and outputs, respectively, can simultaneously improve the effectiveness of semi-supervised node label propagation and node clustering. Our source code is freely available on GitHub.

Alex Morehead, Jeffrey Ruffolo, Aadyot Bhatnagar et al.

Generative models of macromolecules carry abundant and impactful implications for industrial and biomedical efforts in protein engineering. However, existing methods are currently limited to modeling protein structures or sequences, independently or jointly, without regard to the interactions that commonly occur between proteins and other macromolecules. In this work, we introduce MMDiff, a generative model that jointly designs sequences and structures of nucleic acid and protein complexes, independently or in complex, using joint SE(3)-discrete diffusion noise. Such a model has important implications for emerging areas of macromolecular design including structure-based transcription factor design and design of noncoding RNA sequences. We demonstrate the utility of MMDiff through a rigorous new design benchmark for macromolecular complex generation that we introduce in this work. Our results demonstrate that MMDiff is able to successfully generate micro-RNA and single-stranded DNA molecules while being modestly capable of joint modeling DNA and RNA molecules in interaction with multi-chain protein complexes. Source code: https://github.com/Profluent-Internships/MMDiff.

Alex Morehead, Nabin Giri, Jian Liu et al.

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 the latest docking and structure prediction methods within the broadly applicable context of (1) using predicted (apo) protein structures for docking (e.g., for applicability to new proteins); (2) binding multiple (cofactor) ligands concurrently to a given target protein (e.g., for enzyme design); and (3) having no prior knowledge of binding pockets (e.g., for generalization to unknown pockets). To enable a deeper understanding of docking methods' real-world utility, we introduce PoseBench, the first comprehensive benchmark for broadly applicable protein-ligand docking. PoseBench enables researchers to rigorously and systematically evaluate DL methods for apo-to-holo protein-ligand docking and protein-ligand structure prediction using both primary ligand 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 (1) DL co-folding methods generally outperform comparable conventional and DL docking baseline algorithms, yet popular methods such as AlphaFold 3 are still challenged by prediction targets with novel binding poses; (2) certain DL co-folding methods are highly sensitive to their input multiple sequence alignments, while others are not; and (3) DL methods struggle to strike a balance between structural accuracy and chemical specificity when predicting novel or multi-ligand protein targets. Code, data, tutorials, and benchmark results are available at https://github.com/BioinfoMachineLearning/PoseBench.

Alex Morehead, Jianlin Cheng

Powerful generative AI models of protein-ligand structure have recently been proposed, but few of these methods support both flexible protein-ligand docking and affinity estimation. Of those that do, none can directly model multiple binding ligands concurrently or have been rigorously benchmarked on pharmacologically relevant drug targets, hindering their widespread adoption in drug discovery efforts. In this work, we propose FlowDock, the first deep geometric generative model based on conditional flow matching that learns to directly map unbound (apo) structures to their bound (holo) counterparts for an arbitrary number of binding ligands. Furthermore, FlowDock provides predicted structural confidence scores and binding affinity values with each of its generated protein-ligand complex structures, enabling fast virtual screening of new (multi-ligand) drug targets. For the well-known PoseBusters Benchmark dataset, FlowDock outperforms single-sequence AlphaFold 3 with a 51% blind docking success rate using unbound (apo) protein input structures and without any information derived from multiple sequence alignments, and for the challenging new DockGen-E dataset, FlowDock outperforms single-sequence AlphaFold 3 and matches single-sequence Chai-1 for binding pocket generalization. Additionally, in the ligand category of the 16th community-wide Critical Assessment of Techniques for Structure Prediction (CASP16), FlowDock ranked among the top-5 methods for pharmacological binding affinity estimation across 140 protein-ligand complexes, demonstrating the efficacy of its learned representations in virtual screening. Source code, data, and pre-trained models are available at https://github.com/BioinfoMachineLearning/FlowDock.

Hoa La, Ahan Gupta, Alex Morehead et al.

Protein structure prediction models such as AlphaFold3 (AF3) push the frontier of biomolecular modeling by incorporating science-informed architectural changes to the transformer architecture. However, these advances come at a steep system cost, introducing: compute- and memory-intensive operators, 2D attention mechanisms, and retrieval-augmented data pipelines, which collectively hinder the scalability of AF3 training. In this work, we present MegaFold, a cross-platform system to accelerate AF3 training. MegaFold tackles key bottlenecks through ahead-of-time caching to eliminate GPU idle time from the retrieval-augmented data pipeline, Triton-based kernels for memory-efficient EvoAttention on heterogeneous devices, and deep fusion for common and critical small operators in AF3. Evaluation on both NVIDIA H200 and AMD MI250 GPUs shows that MegaFold reduces peak memory usage of AF3 training by up to 1.23$\times$ and improves per-iteration training time by up-to 1.73$\times$ and 1.62$\times$ respectively. More importantly, MegaFold enables training on 1.35$\times$ longer sequence lengths compared to PyTorch baselines without running out-of-memory, significantly improving the scalability of modern protein folding models. We open source our code at https://github.com/Supercomputing-System-AI-Lab/MegaFold/.

Arian R. Jamasb, Alex Morehead, Chaitanya K. Joshi et al.

We introduce ProteinWorkshop, a comprehensive benchmark suite for representation learning on protein structures with Geometric Graph Neural Networks. We consider large-scale pre-training and downstream tasks on both experimental and predicted structures to enable the systematic evaluation of the quality of the learned structural representation and their usefulness in capturing functional relationships for downstream tasks. We find that: (1) large-scale pretraining on AlphaFold structures and auxiliary tasks consistently improve the performance of both rotation-invariant and equivariant GNNs, and (2) more expressive equivariant GNNs benefit from pretraining to a greater extent compared to invariant models. We aim to establish a common ground for the machine learning and computational biology communities to rigorously compare and advance protein structure representation learning. Our open-source codebase reduces the barrier to entry for working with large protein structure datasets by providing: (1) storage-efficient dataloaders for large-scale structural databases including AlphaFoldDB and ESM Atlas, as well as (2) utilities for constructing new tasks from the entire PDB. ProteinWorkshop is available at: github.com/a-r-j/ProteinWorkshop.

Rishabh Anand, Chaitanya K. Joshi, Alex Morehead et al.

We introduce RNA-FrameFlow, the first generative model for 3D RNA backbone design. We build upon SE(3) flow matching for protein backbone generation and establish protocols for data preparation and evaluation to address unique challenges posed by RNA modeling. We formulate RNA structures as a set of rigid-body frames and associated loss functions which account for larger, more conformationally flexible RNA backbones (13 atoms per nucleotide) vs. proteins (4 atoms per residue). Toward tackling the lack of diversity in 3D RNA datasets, we explore training with structural clustering and cropping augmentations. Additionally, we define a suite of evaluation metrics to measure whether the generated RNA structures are globally self-consistent (via inverse folding followed by forward folding) and locally recover RNA-specific structural descriptors. The most performant version of RNA-FrameFlow generates locally realistic RNA backbones of 40-150 nucleotides, over 40% of which pass our validity criteria as measured by a self-consistency TM-score >= 0.45, at which two RNAs have the same global fold. Open-source code: https://github.com/rish-16/rna-backbone-design

Chaitanya K. Joshi, Arian R. Jamasb, Ramon Viñas et al.

Computational RNA design tasks are often posed as inverse problems, where sequences are designed based on adopting a single desired secondary structure without considering 3D conformational diversity. We introduce gRNAde, a geometric RNA design pipeline operating on 3D RNA backbones to design sequences that explicitly account for structure and dynamics. gRNAde uses a multi-state Graph Neural Network and autoregressive decoding to generates candidate RNA sequences conditioned on one or more 3D backbone structures where the identities of the bases are unknown. On a single-state fixed backbone re-design benchmark of 14 RNA structures from the PDB identified by Das et al. (2010), gRNAde obtains higher native sequence recovery rates (56% on average) compared to Rosetta (45% on average), taking under a second to produce designs compared to the reported hours for Rosetta. We further demonstrate the utility of gRNAde on a new benchmark of multi-state design for structurally flexible RNAs, as well as zero-shot ranking of mutational fitness landscapes in a retrospective analysis of a recent ribozyme. Experimental wet lab validation on 10 different structured RNA backbones finds that gRNAde has a success rate of 50% at designing pseudoknotted RNA structures, a significant advance over 35% for Rosetta. Open source code and tutorials are available at: https://github.com/chaitjo/geometric-rna-design

Alex Morehead, Miruna Cretu, Antonia Panescu et al.

General-purpose 3D chemical modeling encompasses molecules and materials, requiring both generative and predictive capabilities. However, most existing AI approaches are optimized for a single domain (molecules or materials) and a single task (generation or prediction), which limits representation sharing and transfer. We introduce Zatom-1, the first foundation model that unifies generative and predictive learning of 3D molecules and materials. Zatom-1 is a Transformer trained with a multimodal flow matching objective that jointly models discrete atom types and continuous 3D geometries. This approach supports scalable pretraining with predictable gains as model capacity increases, while enabling fast and stable sampling. We use joint generative pretraining as a universal initialization for downstream multi-task prediction of properties, energies, and forces. Empirically, Zatom-1 matches or outperforms specialized baselines on both generative and predictive benchmarks, while reducing the generative inference time by more than an order of magnitude. Our experiments demonstrate positive predictive transfer between chemical domains from joint generative pretraining: modeling materials during pretraining improves molecular property prediction accuracy.

Zhiyu Wang, Arian Jamasb, Mustafa Hajij et al.

Protein representation learning (PRL) is crucial for understanding structure-function relationships, yet current sequence- and graph-based methods fail to capture the hierarchical organization inherent in protein structures. We introduce Topotein, a comprehensive framework that applies topological deep learning to PRL through the novel Protein Combinatorial Complex (PCC) and Topology-Complete Perceptron Network (TCPNet). Our PCC represents proteins at multiple hierarchical levels -- from residues to secondary structures to complete proteins -- while preserving geometric information at each level. TCPNet employs SE(3)-equivariant message passing across these hierarchical structures, enabling more effective capture of multi-scale structural patterns. Through extensive experiments on four PRL tasks, TCPNet consistently outperforms state-of-the-art geometric graph neural networks. Our approach demonstrates particular strength in tasks such as fold classification which require understanding of secondary structure arrangements, validating the importance of hierarchical topological features for protein analysis.

Ahmed A. Elhag, Arun Raja, Alex Morehead et al.

Accurate and scalable machine-learned inter-atomic potentials (MLIPs) are essential for molecular simulations ranging from drug discovery to new material design. Current state-of-the-art models enforce roto-translational symmetries through equivariant neural network architectures, a hard-wired inductive bias that can often lead to reduced flexibility, computational efficiency, and scalability. In this work, we introduce TransIP: Transformer-based Inter-Atomic Potentials, a novel training paradigm for interatomic potentials achieving symmetry compliance without explicit architectural constraints. Our approach guides a generic non-equivariant Transformer-based model to learn SO(3)-equivariance by optimizing its representations in the embedding space. Trained on the recent Open Molecules (OMol25) collection, a large and diverse molecular dataset built specifically for MLIPs and covering different types of molecules (including small organics, biomolecular fragments, and electrolyte-like species), TransIP effectively learns symmetry in its latent space, providing low equivariance error. Further, compared to a data augmentation baseline, TransIP achieves 40% to 60% improvement in performance across varying OMol25 dataset sizes. More broadly, our work shows that learned equivariance can be a powerful and efficient alternative to augmentation-based MLIP models.

Alex Morehead, Chen Chen, Jianlin Cheng

Computational methods for predicting the interface contacts between proteins come highly sought after for drug discovery as they can significantly advance the accuracy of alternative approaches, such as protein-protein docking, protein function analysis tools, and other computational methods for protein bioinformatics. In this work, we present the Geometric Transformer, a novel geometry-evolving graph transformer for rotation and translation-invariant protein interface contact prediction, packaged within DeepInteract, an end-to-end prediction pipeline. DeepInteract predicts partner-specific protein interface contacts (i.e., inter-protein residue-residue contacts) given the 3D tertiary structures of two proteins as input. In rigorous benchmarks, DeepInteract, on challenging protein complex targets from the 13th and 14th CASP-CAPRI experiments as well as Docking Benchmark 5, achieves 14% and 1.1% top L/5 precision (L: length of a protein unit in a complex), respectively. In doing so, DeepInteract, with the Geometric Transformer as its graph-based backbone, outperforms existing methods for interface contact prediction in addition to other graph-based neural network backbones compatible with DeepInteract, thereby validating the effectiveness of the Geometric Transformer for learning rich relational-geometric features for downstream tasks on 3D protein structures.

Alex Morehead, Chen Chen, Ada Sedova et al.

How and where proteins interface with one another can ultimately impact the proteins' functions along with a range of other biological processes. As such, precise computational methods for protein interface prediction (PIP) come highly sought after as they could yield significant advances in drug discovery and design as well as protein function analysis. However, the traditional benchmark dataset for this task, Docking Benchmark 5 (DB5), contains only a modest 230 complexes for training, validating, and testing different machine learning algorithms. In this work, we expand on a dataset recently introduced for this task, the Database of Interacting Protein Structures (DIPS), to present DIPS-Plus, an enhanced, feature-rich dataset of 42,112 complexes for geometric deep learning of protein interfaces. The previous version of DIPS contains only the Cartesian coordinates and types of the atoms comprising a given protein complex, whereas DIPS-Plus now includes a plethora of new residue-level features including protrusion indices, half-sphere amino acid compositions, and new profile hidden Markov model (HMM)-based sequence features for each amino acid, giving researchers a large, well-curated feature bank for training protein interface prediction methods. We demonstrate through rigorous benchmarks that training an existing state-of-the-art (SOTA) model for PIP on DIPS-Plus yields SOTA results, surpassing the performance of all other models trained on residue-level and atom-level encodings of protein complexes to date.