Xingyuan Xu

Tianze Zheng, Ailun Wang, Xu Han et al.

A force field is a critical component in molecular dynamics simulations for computational drug discovery. It must achieve high accuracy within the constraints of molecular mechanics' (MM) limited functional forms, which offers high computational efficiency. With the rapid expansion of synthetically accessible chemical space, traditional look-up table approaches face significant challenges. In this study, we address this issue using a modern data-driven approach, developing ByteFF, an Amber-compatible force field for drug-like molecules. To create ByteFF, we generated an expansive and highly diverse molecular dataset at the B3LYP-D3(BJ)/DZVP level of theory. This dataset includes 2.4 million optimized molecular fragment geometries with analytical Hessian matrices, along with 3.2 million torsion profiles. We then trained an edge-augmented, symmetry-preserving molecular graph neural network (GNN) on this dataset, employing a carefully optimized training strategy. Our model predicts all bonded and non-bonded MM force field parameters for drug-like molecules simultaneously across a broad chemical space. ByteFF demonstrates state-of-the-art performance on various benchmark datasets, excelling in predicting relaxed geometries, torsional energy profiles, and conformational energies and forces. Its exceptional accuracy and expansive chemical space coverage make ByteFF a valuable tool for multiple stages of computational drug discovery.

Yi He, Ailun Wang, Zhi Wang et al.

Recent advances in generative models, particularly diffusion and auto-regressive models, have revolutionized fields like computer vision and natural language processing. However, their application to structure-based drug design (SBDD) remains limited due to critical data constraints. To address the limitation of training data for models targeting SBDD tasks, we propose an evolutionary framework named MEVO, which bridges the gap between billion-scale small molecule dataset and the scarce protein-ligand complex dataset, and effectively increase the abundance of training data for generative SBDD models. MEVO is composed of three key components: a high-fidelity VQ-VAE for molecule representation in latent space, a diffusion model for pharmacophore-guided molecule generation, and a pocket-aware evolutionary strategy for molecule optimization with physics-based scoring function. This framework efficiently generate high-affinity binders for various protein targets, validated with predicted binding affinities using free energy perturbation (FEP) methods. In addition, we showcase the capability of MEVO in designing potent inhibitors to KRAS$^{\textrm{G12D}}$, a challenging target in cancer therapeutics, with similar affinity to the known highly active inhibitor evaluated by FEP calculations. With high versatility and generalizability, MEVO offers an effective and data-efficient model for various tasks in structure-based ligand design.

Xingyuan Xu, Mengxi Tan, Bill Corcoran et al.

Convolutional neural networks (CNNs), inspired by biological visual cortex systems, are a powerful category of artificial neural networks that can extract the hierarchical features of raw data to greatly reduce the network parametric complexity and enhance the predicting accuracy. They are of significant interest for machine learning tasks such as computer vision, speech recognition, playing board games and medical diagnosis. Optical neural networks offer the promise of dramatically accelerating computing speed to overcome the inherent bandwidth bottleneck of electronics. Here, we demonstrate a universal optical vector convolutional accelerator operating beyond 10 TeraFLOPS (floating point operations per second), generating convolutions of images of 250,000 pixels with 8 bit resolution for 10 kernels simultaneously, enough for facial image recognition. We then use the same hardware to sequentially form a deep optical CNN with ten output neurons, achieving successful recognition of full 10 digits with 900 pixel handwritten digit images with 88% accuracy. Our results are based on simultaneously interleaving temporal, wavelength and spatial dimensions enabled by an integrated microcomb source. This approach is scalable and trainable to much more complex networks for demanding applications such as unmanned vehicle and real-time video recognition.