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/. A summary of this paper appears in the proceedings of the RECOMB 2014 conference, April 2–5.
Sequence-based protein homology detection has been extensively studied, but it remains very challenging for remote homologs with divergent sequences. So far the most sensitive methods employ HMM-HMM comparison, which models a protein family using HMM (Hidden Markov Model) and then detects homologs using HMM-HMM alignment. HMM cannot model long-range residue interaction patterns and thus, carries very little information regarding the global 3D structure of a protein family. As such, HMM comparison is not sensitive enough for distantly-related homologs. In this paper, we present an MRF-MRF comparison method for homology detection. In particular, we model a protein family using Markov Random Fields (MRF) and then detect homologs by MRF-MRF alignment. Compared to HMM, MRFs are able to model long-range residue interaction pattern and thus, contains information for the overall 3D structure of a protein family. Consequently, MRF-MRF comparison is much more sensitive than HMM-HMM comparison. To implement MRF-MRF comparison, we have developed a new scoring function to measure the similarity of two MRFs and also an efficient ADMM algorithm to optimize the scoring function. Experiments confirm that MRF-MRF comparison indeed outperforms HMM-HMM comparison in terms of both alignment accuracy and remote homology detection, especially for mainly beta proteins.