Proteins are the major building blocks of life, and actuators of almost all chemical and biophysical events in living organisms. Their native structures in turn enable their biological functions which have a fundamental role in drug design. This motivates predicting the structure of a protein from its sequence of amino acids, a fundamental problem in computational biology. In this work, we demonstrate state-of-the-art protein structure prediction (PSP) results using embeddings and deep learning models for prediction of backbone atom distance matrices and torsion angles. We recover 3D coordinates of backbone atoms and reconstruct full atom protein by optimization. We create a new gold standard dataset of proteins which is comprehensive and easy to use. Our dataset consists of amino acid sequences, Q8 secondary structures, position specific scoring matrices, multiple sequence alignment co-evolutionary features, backbone atom distance matrices, torsion angles, and 3D coordinates. We evaluate the quality of our structure prediction by RMSD on the latest Critical Assessment of Techniques for Protein Structure Prediction (CASP) test data and demonstrate competitive results with the winning teams and AlphaFold in CASP13 and supersede the results of the winning teams in CASP12. We make our data, models, and code publicly available.
The inverse Potts problem to infer a Boltzmann distribution for homologous protein sequences from their single-site and pairwise amino acid frequencies recently attracts a great deal of attention in the studies of protein structure and evolution. We study regularization and learning methods and how to tune regularization parameters to correctly infer interactions in Boltzmann machine learning. Using $L_2$ regularization for fields, group $L_1$ for couplings is shown to be very effective for sparse couplings in comparison with $L_2$ and $L_1$. Two regularization parameters are tuned to yield equal values for both the sample and ensemble averages of evolutionary energy. Both averages smoothly change and converge, but their learning profiles are very different between learning methods. The Adam method is modified to make stepsize proportional to the gradient for sparse couplings. It is shown by first inferring interactions from protein sequences and then from Monte Carlo samples that the fields and couplings can be well recovered, but that recovering the pairwise correlations in the resolution of a total energy is harder for the natural proteins than for the protein-like sequences. Selective temperature for folding/structural constrains in protein evolution is also estimated.
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.
Publishing datasets plays an essential role in open data research and promoting transparency of government agencies. However, such data publication might reveal users' private information. One of the most sensitive sources of data is spatiotemporal trajectory datasets. Unfortunately, merely removing unique identifiers cannot preserve the privacy of users. Adversaries may know parts of the trajectories or be able to link the published dataset to other sources for the purpose of user identification. Therefore, it is crucial to apply privacy preserving techniques before the publication of spatiotemporal trajectory datasets. In this paper, we propose a robust framework for the anonymization of spatiotemporal trajectory datasets termed as machine learning based anonymization (MLA). By introducing a new formulation of the problem, we are able to apply machine learning algorithms for clustering the trajectories and propose to use $k$-means algorithm for this purpose. A variation of $k$-means algorithm is also proposed to preserve the privacy in overly sensitive datasets. Moreover, we improve the alignment process by considering multiple sequence alignment as part of the MLA. The framework and all the proposed algorithms are applied to TDrive and Geolife location datasets. The experimental results indicate a significantly higher utility of datasets by anonymization based on MLA framework.
We present an extension of Felsenstein's algorithm to indel models defined on entire sequences, without the need to condition on one multiple alignment. The algorithm makes use of a generalization from probabilistic substitution matrices to weighted finite-state transducers. Our approach may equivalently be viewed as a probabilistic formulation of progressive multiple sequence alignment, using partial-order graphs to represent ensemble profiles of ancestral sequences. We present a hierarchical stochastic approximation technique which makes this algorithm tractable for alignment analyses of reasonable size.
Sequence-based protein homology detection has been extensively studied and so far the most sensitive method is based upon comparison of protein sequence profiles, which are derived from multiple sequence alignment (MSA) of sequence homologs in a protein family. A sequence profile is usually represented as a position-specific scoring matrix (PSSM) or an HMM (Hidden Markov Model) and accordingly PSSM-PSSM or HMM-HMM comparison is used for homolog detection. This paper presents a new homology detection method MRFalign, consisting of three key components: 1) a Markov Random Fields (MRF) representation of a protein family; 2) a scoring function measuring similarity of two MRFs; and 3) an efficient ADMM (Alternating Direction Method of Multipliers) algorithm aligning two MRFs. Compared to HMM that can only model very short-range residue correlation, MRFs can model long-range residue interaction pattern and thus, encode information for the global 3D structure of a protein family. Consequently, MRF-MRF comparison for remote homology detection shall be much more sensitive than HMM-HMM or PSSM-PSSM comparison. Experiments confirm that MRFalign outperforms several popular HMM or PSSM-based methods in terms of both alignment accuracy and remote homology detection and that MRFalign works particularly well for mainly beta proteins. For example, tested on the benchmark SCOP40 (8353 proteins) for homology detection, PSSM-PSSM and HMM-HMM succeed on 48% and 52% of proteins, respectively, at superfamily level, and on 15% and 27% of proteins, respectively, at fold level. In contrast, MRFalign succeeds on 57.3% and 42.5% of proteins at superfamily and fold level, respectively. This study implies that long-range residue interaction patterns are very helpful for sequence-based homology detection. The software is available for download at http://raptorx.uchicago.edu/download/.
Alignment-free sequence analysis approaches provide important alternatives over multiple sequence alignment (MSA) in biological sequence analysis because alignment-free approaches have low computation complexity and are not dependent on high level of sequence identity, however, most of the existing alignment-free methods do not employ true full information content of sequences and thus can not accurately reveal similarities and differences among DNA sequences. We present a novel alignment-free computational method for sequence analysis based on Ramanujan-Fourier transform (RFT), in which complete information of DNA sequences is retained. We represent DNA sequences as four binary indicator sequences and apply RFT on the indicator sequences to convert them into frequency domain. The Euclidean distance of the complete RFT coefficients of DNA sequences are used as similarity measure. To address the different lengths in Euclidean space of RFT coefficients, we pad zeros to short DNA binary sequences so that the binary sequences equal the longest length in the comparison sequence data. Thus, the DNA sequences are compared in the same dimensional frequency space without information loss. We demonstrate the usefulness of the proposed method by presenting experimental results on hierarchical clustering of genes and genomes. The proposed method opens a new channel to biological sequence analysis, classification, and structural module identification.
Many biological questions, including the estimation of deep evolutionary histories and the detection of remote homology between protein sequences, rely upon multiple sequence alignments (MSAs) and phylogenetic trees of large datasets. However, accurate large-scale multiple sequence alignment is very difficult, especially when the dataset contains fragmentary sequences. We present UPP, an MSA method that uses a new machine learning technique - the Ensemble of Hidden Markov Models - that we propose here. UPP produces highly accurate alignments for both nucleotide and amino acid sequences, even on ultra-large datasets or datasets containing fragmentary sequences. UPP is available at https://github.com/smirarab/sepp.
A profile comparison method with position-specific scoring matrix (PSSM) is one of the most accurate alignment methods. Currently, cosine similarity and correlation coefficient are used as scoring functions of dynamic programming to calculate similarity between PSSMs. However, it is unclear that these functions are optimal for profile alignment methods. At least, by definition, these functions cannot capture non-linear relationships between profiles. Therefore, in this study, we attempted to discover a novel scoring function, which was more suitable for the profile comparison method than the existing ones. Firstly we implemented a new derivative free neural network by combining the conventional neural network with evolutionary strategy optimization method. Next, using the framework, the scoring function was optimized for aligning remote sequence pairs. Nepal, the pairwise profile aligner with the novel scoring function significantly improved both alignment sensitivity and precision, compared to aligners with the existing functions. Nepal improved alignment quality because of adaptation to remote sequence alignment and increasing the expressive power of similarity score. The novel scoring function can be realized using a simple matrix operation and easily incorporated into other aligners. With our scoring function, the performance of homology detection and/or multiple sequence alignment for remote homologous sequences would be further improved.