We propose a novel neural network-based approach to modeling protein dynamics using an implicit representation of a protein's surface in 3D and time.

We propose a novel neural network-based approach to modeling protein dynamics using an implicit representation of a protein's surface in 3D and time.

Fragment-based drug design is a promising strategy leveraging the binding of small chemical moieties that can efficiently guide drug discovery. The initial step of fragment identification remains challenging, as fragments often bind weakly and non-specifically. We developed a protein-fragment encoder that relies on a contrastive learning approach to map both molecular fragments and protein surfaces in a shared latent space. The encoder captures interaction-relevant features and allows to perform virtual screening as well as generative design with our new method LatentFrag. In LatentFrag, fragment embeddings and positions are generated conditioned on the protein surface while being chemically realistic by construction. Our expressive fragment and protein representations allow location of protein-fragment interaction sites with high sensitivity and we observe state-of-the-art fragment recovery rates when sampling from the learned distribution of latent fragment embeddings. Our generative method outperforms common methods such as virtual screening at a fraction of its computational cost providing a valuable starting point for fragment hit discovery. We further show the practical utility of LatentFrag and extend the workflow to full ligand design tasks. Together, these approaches contribute to advancing fragment identification and provide valuable tools for fragment-based drug discovery.

Protein design and engineering has become a crucial component of pharmaceutical research and development, finding application in a wide variety of diagnostic and industrial settings.

Drug-protein binding and dissociation dynamics are fundamental to understanding molecular interactions in biological systems. While many tools for drug-protein interaction studies have emerged, especially artificial intelligence (AI)-based generative models, predictive tools on binding/dissociation kinetics and dynamics are still limited. We propose a novel research paradigm that combines molecular dynamics (MD) simulations, enhanced sampling, and AI generative models to address this issue. We propose an enhanced sampling strategy to efficiently implement the drug-protein dissociation process in MD simulations and estimate the free energy surface (FES). We constructed a program pipeline of MD simulations based on this sampling strategy, thus generating a dataset including 26,612 drug-protein dissociation trajectories containing about 13 million frames. We named this dissociation dynamics dataset DD-13M and used it to train a deep equivariant generative model UnbindingFlow, which can generate collision-free dissociation trajectories. The DD-13M database and UnbindingFlow model represent a significant advancement in computational structural biology, and we anticipate its broad applicability in machine learning studies of drug-protein interactions. Our ongoing efforts focus on expanding this methodology to encompass a broader spectrum of drug-protein complexes and exploring novel applications in pathway prediction.

Predicting interactions between proteins is one of the most important yet challenging problems in structural bioinformatics. Intrinsically, potential function sites in protein surfaces are determined by both geometric and chemical features. However, existing works only consider handcrafted or individually learned chemical features from the atom type and extract geometric features independently. Here, we identify two key properties of effective protein surface learning: 1) relationship among atoms: atoms are linked with each other by covalent bonds to form biomolecules instead of appearing alone, leading to the significance of modeling the relationship among atoms in chemical feature learning. 2) hierarchical feature interaction: the neighboring residue effect validates the significance of hierarchical feature interaction among atoms and between surface points and atoms (or residues). In this paper, we present a principled framework based on deep learning techniques, namely Hierarchical Chemical and Geometric Feature Interaction Network (HCGNet), for protein surface analysis by bridging chemical and geometric features with hierarchical interactions. Extensive experiments demonstrate that our method outperforms the prior state-of-the-art method by 2.3% in site prediction task and 3.2% in interaction matching task, respectively. Our code is available at https://github.com/xmed-lab/HCGNet.