Biology subjects

Skolnick, J.

Publications and source records attributed to Skolnick, J..

4 recordsLinked to original sources

bioRxiv2022

Deep learning-driven insights into super protein complexes for outer membrane protein biogenesis in bacteria

To reach their final destinations, outer membrane proteins (OMPs) of gram-negative bacteria undertake an eventful journey beginning in the cytosol. Multiple molecular machines, chaperones, proteases, and other enzymes facilitate the translocation and assembly of OMPs. These helpers usually associate, often transiently, forming large protein assemblies. They are not well-understood due to experimental challenges in capturing and characterizing protein-protein interactions (PPIs), especially transient ones. Using AF2Complex, we introduce a high-throughput, deep learning pipeline to identify PPIs within the E. coli cell envelope and apply it to several proteins from an OMP biogenesis pathway. Among the top confident hits obtained from screening ~1,500 envelope proteins, we find not only expected interactions but also unexpected ones with profound implications. Subsequently, we predict atomic structures for these protein complexes. These structures, typically of high confidence, explain experimental observations, and lead to mechanistic hypotheses for how a chaperone assists a nascent, precursor OMP emerging from a translocon, how another chaperone prevents it from aggregating and docks to an {beta}-barrel assembly port, and how a protease performs quality control. This work presents a general strategy for investigating biological pathways by using structural insights gained from deep learning-based predictions.

molecular biology↗

bioRxiv2022

Prediction of inter-chain distance maps of protein complexes with 2D attention-based deep neural networks

Residue-residue distance information is useful for predicting the tertiary structures of protein monomers or the quaternary structures of protein complexes. Many deep learning methods have been developed to predict intra-chain residue-residue distances of monomers accurately, but very few methods can accurately predict inter-chain residue-residue distances of protein complexes. We develop a new deep learning method CDPred (i.e., Complex Distance Prediction) based on the 2D attention-powered residual network architecture to address the gap. CDPred predicts the inter-chain distance maps of dimers (homodimers or heterodimers) from the features extracted from multiple sequence alignments (MSAs) and the intra-chain distance maps of predicted tertiary structures of monomers. Tested on two homodimer test datasets, CDPred achieves the precision of 61.56% and 43.26% for top L/5 inter-chain contact predictions (L: length of the monomer in homodimer), respectively, which is substantially higher than DeepHomos 37.40% and 23.08% and GLINTERs 48.09% and 36.74%. And tested on the two heterodimer test datasets, the top L/5 inter-chain contact prediction precision (L: length of the shorter monomer in heterodimer) of CDPred is 47.59% and 22.87% respectively, which surpasses GLINTERs 23.24% and 13.49%. Moreover, we demonstrate that the residue-residue co-evolutionary features calculated from multiple sequence alignments by a deep learning language model are more informative for the inter-chain contact prediction than the traditional statistical optimization approach of maximizing direct co-evolutionary signals, and large intra-chain distances in the intra-chain distance maps of monomers are more useful for the inter-chain distance prediction than small intra-chain distances.

bioinformatics↗

bioRxiv2021

Predicting direct physical interactions in multimeric proteins with deep learning

Accurate descriptions of protein-protein interactions are essential for understanding biological systems. Remarkably accurate atomic structures have been recently computed for individual proteins by AlphaFold2 (AF2). Here, we demonstrate that the same neural network models from AF2 developed for single protein sequences can be adapted to predict the structures of multimeric protein complexes without retraining. In contrast to common approaches, our method, AF2Complex, does not require paired multiple sequence alignments. It achieves higher accuracy than some complex protein-protein docking strategies and provides a significant improvement over AF-Multimer, a new development of AlphaFold for multimeric proteins. Moreover, we introduce metrics for predicting direct protein-protein interactions between arbitrary protein pairs and validate AF2Complex on some challenging benchmark sets and the E. coli proteome. Lastly, using the cytochrome c biogenesis system I as an example, we present high-confidence models of three sought-after assemblies formed by eight members of this system.

bioinformatics↗

bioRxiv2021

A general framework to learn tertiary structure for protein sequence annotation

During the past five years, deep-learning algorithms have enabled ground-breaking progress towards the prediction of tertiary structure from a protein sequence. Very recently, we developed SAdLSA, a new computational algorithm for protein sequence comparison via deep-learning of protein structural alignments. SAdLSA shows significant improvement over established sequence alignment methods. In this contribution, we show that SAdLSA provides a general machine-learning framework for structurally characterizing protein sequences. By aligning a protein sequence against itself, SAdLSA generates a fold distogram for the input sequence, including challenging cases whose structural folds were not present in the training set. About 70% of the predicted distograms are statistically significant. Although at present the accuracy of the intra-sequence distogram predicted by SAdLSA self-alignment is not as good as deep-learning algorithms specifically trained for distogram prediction, it is remarkable that the prediction of single protein structures is encoded by an algorithm that learns ensembles of pairwise structural comparisons, without being explicitly trained to recognize individual structural folds. As such, SAdLSA can not only predict protein folds for individual sequences, but also detects subtle, yet significant, structural relationships between multiple protein sequences using the same deep-learning neural network. The former reduces to a special case in this general framework for protein sequence annotation.

bioinformatics↗