Daily Papers

Peptides, short chains of amino acid residues, play a vital role in numerous biological processes by interacting with other target molecules, offering substantial potential in drug discovery. In this work, we present PepFlow, the first multi-modal deep generative model grounded in the flow-matching framework for the design of full-atom peptides that target specific protein receptors. Drawing inspiration from the crucial roles of residue backbone orientations and side-chain dynamics in protein-peptide interactions, we characterize the peptide structure using rigid backbone frames within the SE(3) manifold and side-chain angles on high-dimensional tori. Furthermore, we represent discrete residue types in the peptide sequence as categorical distributions on the probability simplex. By learning the joint distributions of each modality using derived flows and vector fields on corresponding manifolds, our method excels in the fine-grained design of full-atom peptides. Harnessing the multi-modal paradigm, our approach adeptly tackles various tasks such as fix-backbone sequence design and side-chain packing through partial sampling. Through meticulously crafted experiments, we demonstrate that PepFlow exhibits superior performance in comprehensive benchmarks, highlighting its significant potential in computational peptide design and analysis.

Accurately modeling protein 3D structure is essential for the design of functional proteins. An important sub-task of structure modeling is protein side-chain packing: predicting the conformation of side-chains (rotamers) given the protein's backbone structure and amino-acid sequence. Conventional approaches for this task rely on expensive sampling procedures over hand-crafted energy functions and rotamer libraries. Recently, several deep learning methods have been developed to tackle the problem in a data-driven way, albeit with vastly different formulations (from image-to-image translation to directly predicting atomic coordinates). Here, we frame the problem as a joint regression over the side-chains' true degrees of freedom: the dihedral chi angles. We carefully study possible objective functions for this task, while accounting for the underlying symmetries of the task. We propose Holographic Packer (H-Packer), a novel two-stage algorithm for side-chain packing built on top of two light-weight rotationally equivariant neural networks. We evaluate our method on CASP13 and CASP14 targets. H-Packer is computationally efficient and shows favorable performance against conventional physics-based algorithms and is competitive against alternative deep learning solutions.

Protein structure prediction is pivotal for understanding the structure-function relationship of proteins, advancing biological research, and facilitating pharmaceutical development and experimental design. While deep learning methods and the expanded availability of experimental 3D protein structures have accelerated structure prediction, the dynamic nature of protein structures has received limited attention. This study introduces an innovative 4D diffusion model incorporating molecular dynamics (MD) simulation data to learn dynamic protein structures. Our approach is distinguished by the following components: (1) a unified diffusion model capable of generating dynamic protein structures, including both the backbone and side chains, utilizing atomic grouping and side-chain dihedral angle predictions; (2) a reference network that enhances structural consistency by integrating the latent embeddings of the initial 3D protein structures; and (3) a motion alignment module aimed at improving temporal structural coherence across multiple time steps. To our knowledge, this is the first diffusion-based model aimed at predicting protein trajectories across multiple time steps simultaneously. Validation on benchmark datasets demonstrates that our model exhibits high accuracy in predicting dynamic 3D structures of proteins containing up to 256 amino acids over 32 time steps, effectively capturing both local flexibility in stable states and significant conformational changes.

Visual place recognition (VPR) is critical in not only localization and mapping for autonomous driving vehicles, but also in assistive navigation for the visually impaired population. To enable a long-term VPR system on a large scale, several challenges need to be addressed. First, different applications could require different image view directions, such as front views for self-driving cars while side views for the low vision people. Second, VPR in metropolitan scenes can often cause privacy concerns due to the imaging of pedestrian and vehicle identity information, calling for the need for data anonymization before VPR queries and database construction. Both factors could lead to VPR performance variations that are not well understood yet. To study their influences, we present the NYU-VPR dataset that contains more than 200,000 images over a 2km by 2km area near the New York University campus, taken within the whole year of 2016. We present benchmark results on several popular VPR algorithms showing that side views are significantly more challenging for current VPR methods while the influence of data anonymization is almost negligible, together with our hypothetical explanations and in-depth analysis.

Ligand molecule conformation generation is a critical challenge in drug discovery. Deep learning models have been developed to tackle this problem, particularly through the use of generative models in recent years. However, these models often generate conformations that lack meaningful structure and randomness due to the absence of essential side information. Examples of such side information include the chemical and geometric features of the target protein, ligand-target compound interactions, and ligand chemical properties. Without these constraints, the generated conformations may not be suitable for further selection and design of new drugs. To address this limitation, we propose a novel method for generating ligand conformations that leverage side information and incorporate flexible constraints into standard diffusion models. Drawing inspiration from the concept of message passing, we introduce ligand-target massage passing block, a mechanism that facilitates the exchange of information between target nodes and ligand nodes, thereby incorporating target node features. To capture non-covalent interactions, we introduce ligand-target compound inter and intra edges. To further improve the biological relevance of the generated conformations, we train energy models using scalar chemical features. These models guide the progress of the standard Denoising Diffusion Probabilistic Models, resulting in more biologically meaningful conformations. We evaluate the performance of SIDEGEN using the PDBBind-2020 dataset, comparing it against other methods. The results demonstrate improvements in both Aligned RMSD and Ligand RMSD evaluations. Specifically, our model outperforms GeoDiff (trained on PDBBind-2020) by 20% in terms of the median aligned RMSD metric.

Graph neural networks are emerging as promising methods for modeling molecular graphs, in which nodes and edges correspond to atoms and chemical bonds, respectively. Recent studies show that when 3D molecular geometries, such as bond lengths and angles, are available, molecular property prediction tasks can be made more accurate. However, computing of 3D molecular geometries requires quantum calculations that are computationally prohibitive. For example, accurate calculation of 3D geometries of a small molecule requires hours of computing time using density functional theory (DFT). Here, we propose to predict the ground-state 3D geometries from molecular graphs using machine learning methods. To make this feasible, we develop a benchmark, known as Molecule3D, that includes a dataset with precise ground-state geometries of approximately 4 million molecules derived from DFT. We also provide a set of software tools for data processing, splitting, training, and evaluation, etc. Specifically, we propose to assess the error and validity of predicted geometries using four metrics. We implement two baseline methods that either predict the pairwise distance between atoms or atom coordinates in 3D space. Experimental results show that, compared with generating 3D geometries with RDKit, our method can achieve comparable prediction accuracy but with much smaller computational costs. Our Molecule3D is available as a module of the MoleculeX software library (https://github.com/divelab/MoleculeX).

Networks of atom-centered coordination octahedra commonly occur in inorganic and hybrid solid-state materials. Characterizing their spatial arrangements and characteristics is crucial for relating structures to properties for many materials families. The traditional method using case-by-case inspection becomes prohibitive for discovering trends and similarities in large datasets. Here, we operationalize chemical intuition to automate the geometric parsing, quantification, and classification of coordination octahedral networks. We find axis-resolved tilting trends in ABO_{3} perovskite polymorphs, which assist in detecting oxidation state changes. Moreover, we develop a scale-invariant encoding scheme to represent these networks, which, combined with human-assisted unsupervised machine learning, allows us to taxonomize the inorganic framework polytypes in hybrid iodoplumbates (A_xPb_yI_z). Consequently, we uncover a violation of Pauling's third rule and the design principles underpinning their topological diversity. Our results offer a glimpse into the vast design space of atomic octahedral networks and inform high-throughput, targeted screening of specific structure types.