Comprehensive assessment of protein loop modeling programs on large-scale datasets: prediction accuracy and efficiency.

Protein loops play a critical role in the dynamics of proteins and are essential for numerous biological functions, and various computational approaches to loop modeling have been proposed over the past decades. However, a comprehensive understanding of the strengths and weaknesses of each method is lacking. In this work, we constructed two high-quality datasets (i.e. the General dataset and the CASP dataset) and systematically evaluated the accuracy and efficiency of 13 commonly used loop modeling approaches from the perspective of loop lengths, protein classes and residue types. The results indicate that the knowledge-based method FREAD generally outperforms the other tested programs in most cases, but encountered challenges when predicting loops longer than 15 and 30 residues on the CASP and General datasets, respectively. The ab initio method Rosetta NGK demonstrated exceptional modeling accuracy for short loops with four to eight residues and achieved the highest success rate on the CASP dataset. The well-known AlphaFold2 and RoseTTAFold require more resources for better performance, but they exhibit promise for predicting loops longer than 16 and 30 residues in the CASP and General datasets. These observations can provide valuable insights for selecting suitable methods for specific loop modeling tasks and contribute to future advancements in the field.

Highly Accurate and Efficient Deep Learning Paradigm for Full-Atom Protein Loop Modeling with KarmaLoop.

Protein loop modeling is a challenging yet highly nontrivial task in protein structure prediction. Despite recent progress, existing methods including knowledge-based, ab initio, hybrid, and deep learning (DL) methods fall substantially short of either atomic accuracy or computational efficiency. To overcome these limitations, we present KarmaLoop, a novel paradigm that distinguishes itself as the first DL method centered on full-atom (encompassing both backbone and side-chain heavy atoms) protein loop modeling. Our results demonstrate that KarmaLoop considerably outperforms conventional and DL-based methods of loop modeling in terms of both accuracy and efficiency, with the average RMSDs of 1.77 and 1.95 Å for the CASP13+14 and CASP15 benchmark datasets, respectively, and manifests at least 2 orders of magnitude speedup in general compared with other methods. Consequently, our comprehensive evaluations indicate that KarmaLoop provides a state-of-the-art DL solution for protein loop modeling, with the potential to hasten the advancement of protein engineering, antibody-antigen recognition, and drug design.

Efficient and accurate large library ligand docking with KarmaDock.

Ligand docking is one of the core technologies in structure-based virtual screening for drug discovery. However, conventional docking tools and existing deep learning tools may suffer from limited performance in terms of speed, pose quality and binding affinity accuracy. Here we propose KarmaDock, a deep learning approach for ligand docking that integrates the functions of docking acceleration, binding pose generation and correction, and binding strength estimation. The three-stage model consists of the following components: (1) encoders for the protein and ligand to learn the representations of intramolecular interactions; (2) E(n) equivariant graph neural networks with self-attention to update the ligand pose based on both protein-ligand and intramolecular interactions, followed by post-processing to ensure chemically plausible structures; (3) a mixture density network for scoring the binding strength. KarmaDock was validated on four benchmark datasets and tested in a real-world virtual screening project that successfully identified experiment-validated active inhibitors of leukocyte tyrosine kinase (LTK).