Following this thought, we recast virtual screening as an information retrieval task, i.e., given a

Predicting protein properties is paramount for biological and medical advancements. Current protein engineering mutates on a typical protein, called the wild-type, to construct a family of homologous proteins and study their properties. Yet, existing methods easily neglect subtle mutations, failing to capture the effect on the protein properties. To this end, we propose EvolMPNN, Evolution-aware Message Passing Neural Network, an efficient model to learn evolution-aware protein embeddings. EvolMPNN samples sets of anchor proteins, computes evolutionary information by means of residues and employs a differentiable evolution-aware aggregation scheme over these sampled anchors. This way, EvolMPNN can efficiently utilise a novel message-passing method to capture the mutation effect on proteins with respect to the anchor proteins. Afterwards, the aggregated evolution-aware embeddings are integrated with sequence embeddings to generate final comprehensive protein embeddings. Our model shows up to 6.4% better than state-of-the-art methods and attains 36X inference speedup in comparison with large pre-trained models. Code and models are available at https://github.com/zhiqiangzhongddu/EvolMPNN.

Virtual screening, which identifies potential drugs from vast compound databases to bind with a particular protein pocket, is a critical step in AI-assisted drug discovery. Traditional docking methods are highly time-consuming, and can only work with a restricted search library in real-life applications. Recent supervised learning approaches using scoring functions for binding-affinity prediction, although promising, have not yet surpassed docking methods due to their strong dependency on limited data with reliable binding-affinity labels. In this paper, we propose a novel contrastive learning framework, DrugCLIP, by reformulating virtual screening as a dense retrieval task and employing contrastive learning to align representations of binding protein pockets and molecules from a large quantity of pairwise data without explicit binding-affinity scores. We also introduce a biological-knowledge inspired data augmentation strategy to learn better protein-molecule representations. Extensive experiments show that DrugCLIP significantly outperforms traditional docking and supervised learning methods on diverse virtual screening benchmarks with highly reduced computation time, especially in zero-shot setting.

The single-particle cryo-EM field faces the persistent challenge of preferred orientation, lacking general computational solutions. We introduce cryoPROS, an AI-based approach designed to address the above issue. By generating the auxiliary particles with a conditional deep generative model, cryoPROS addresses the intrinsic bias in orientation estimation for the observed particles. We effectively employed cryoPROS in the cryo-EM single particle analysis of the hemagglutinin trimer, showing the ability to restore the near-atomic resolution structure on non-tilt data. Moreover, the enhanced version named cryoPROS-MP significantly improves the resolution of the membrane protein NaX using the no-tilted data that contains the effects of micelles. Compared to the classical approaches, cryoPROS does not need special experimental or image acquisition techniques, providing a purely computational yet effective solution for the preferred orientation problem. Finally, we conduct extensive experiments that establish the low risk of model bias and the high robustness of cryoPROS.

Protein secondary structure prediction (PSSP) is essential for protein function analysis. However, for low homologous proteins, the PSSP suffers from insufficient input features. In this paper, we explicitly import external self-supervised knowledge for low homologous PSSP under the guidance of residue-wise profile fusion. In practice, we firstly demonstrate the superiority of profile over Position-Specific Scoring Matrix (PSSM) for low homologous PSSP. Based on this observation, we introduce the novel self-supervised BERT features as the pseudo profile, which implicitly involves the residue distribution in all native discovered sequences as the complementary features. Further-more, a novel residue-wise attention is specially designed to adaptively fuse different features (i.e.,original low-quality profile, BERT based pseudo profile), which not only takes full advantage of each feature but also avoids noise disturbance. Be-sides, the feature consistency loss is proposed to accelerate the model learning from multiple semantic levels. Extensive experiments confirm that our method outperforms state-of-the-arts (i.e.,4.7%forextremely low homologous cases on BC40 dataset).

Sequence set is a widely-used type of data source in a large variety of fields. A typical example is protein structure prediction, which takes an multiple sequence alignment (MSA) as input and aims to infer structural information from it. Almost all of the existing approaches exploit MSAs in an indirect fashion, i.e., they transform MSAs into position-specific scoring matrices (PSSM) that represent the distribution of amino acid types at each column. PSSM could capture column-wise characteristics of MSA, however, the column-wise characteristics embedded in each individual component sequence were nearly totally neglected. The drawback of PSSM is rooted in the fact that an MSA is essentially an unordered sequence set rather than a matrix. Specifically, the interchange of any two sequences will not affect the whole MSA. In contrast, the pixels in an image essentially form a matrix since any two rows of pixels cannot be interchanged. Therefore, the traditional deep neural networks designed for image processing cannot be directly applied on sequence sets. Here, we proposed a novel deep neural network framework (called Seq-SetNet) for sequence set processing. By employing a {\it symmetric function} module to integrate features calculated from preceding layers, Seq-SetNet are immune to the order of sequences in the input MSA. This advantage enables us to directly and fully exploit MSAs by considering each component protein individually. We evaluated Seq-SetNet by using it to extract structural information from MSA for protein secondary structure prediction. Experimental results on popular benchmark sets suggests that Seq-SetNet outperforms the state-of-the-art approaches by 3.6% in precision. These results clearly suggest the advantages of Seq-SetNet in sequence set processing and it can be readily used in a wide range of fields, say natural language processing.

An ensemble of models (EM), where each model is constructed on a diverse subset of feature variables, is proposed to rank rare class items ahead of majority class items in a highly unbalanced two class problem. The proposed ensemble relies on an algorithm to group the feature variables into subsets where the variables in a subset work better together in a model and the variables in different subsets work better in separate models. The strength of the EM depends on the algorithm's ability to identify strong and diverse subsets of feature variables. A second phase of ensembling is achieved by aggregating several EMs each optimized on a diverse evaluation metric. The resulting ensemble is called ensemble of models and metrics (EMM). Here, the diverse/complementary evaluation metrics ensure increased diversity among EMs to aggregate. The ensembles are applied to the protein homology data, downloaded from the 2004 KDD cup competition website, to rank proteins in such a way that the rare homologous proteins are found ahead of the majority non-homologous proteins. The ensembles are constructed using feature variables which are various scores from sequence alignments of amino acids in a candidate protein and three dimensional descriptions of a native protein representing functional and structural similarity of proteins. While prediction performances of the EMs are better than the contemporary state-of-the-art ensembles and competitive to the winning procedures of the $2004$ KDD cup competition, the performances of the EMM are found on the top of all. In this application, we have two diverse EMs constructed on two complementary evaluation metrics average precision and rank last, where the former is robust against ranking close homologs and the latter is robust against ranking distant homologs. The advantage of using EMM is that it is robust against both close and distant homologs.