Proteins play a central role in all biological processes. Akin to the complete sequencing of genomes, complete description of protein structures is a fundamental step towards understanding biological life, and is also highly relevant medically in the development of therapeutics and drugs. The broad, long-term goal of the project is to develop machine learning methods for data-driven protein structure prediction through two independent but complementary strategies: 1) much more accurate template-based modeling for proteins with remote homologs in the Protein Data Bank and 2) better template-free modeling method for proteins without detectable templates and for improving template-based models.
The specific aims are:
Aim 1) to greatly improve template-based modeling by 1a) improving protein sequence-template alignment using a regression-tree-based nonlinear scoring function, especially when good sequence profiles are unavailable;and 1b) improving fold recognition using a machine learning method to combine both residue-level and atom-level features;
Aim 2) to improve protein conformation sampling in a continuous space and thus template-free modeling by three independent but complementary approaches: 2a) modeling nonlinear sequence- structure relationship using Conditional (Markov) Random Fields (CRF) models;2b) simultaneously sampling secondary and tertiary structure;and 2c) learning structure information from template. The core of the project is to develop various CRF models for data-driven protein structure prediction, by learning protein sequence-structure relationship from existing sequence/structure databases. The product of this research includes a regression-tree-based CRF model for accurate protein alignment, especially for proteins without close homologs in the PDB or without very good sequence profiles;a SVM model for protein fold recognition;a few CRF models for efficient protein conformation sampling in a continuous space;and a complete protein structure prediction software package. Also, it will produce a web server publicly available for various academic and biomedical users. Protein structure prediction will lead to a broad range of biomedical applications, such as the development of novel diagnostics, better understanding of disease processes and improved preventive therapies leading to reduced health care costs. Protein modeling is also widely applied in the pharmaceutical industry and integrated into most stages of pharmaceutical research.

Public Health Relevance

Novel protein structure prediction will lead to a broad range of biomedical applications, such as the development of novel diagnostics, better understanding of disease processes and improved preventive therapies leading to reduced health care costs. Protein modeling is also widely applied in the pharmaceutical industry and integrated into most stages of pharmaceutical research.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM089753-03
Application #
8269822
Study Section
Biodata Management and Analysis Study Section (BDMA)
Program Officer
Lyster, Peter
Project Start
2010-05-14
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$265,869
Indirect Cost
$72,819
Name
Toyota Technological Institute / Chicago
Department
Type
DUNS #
127228927
City
Chicago
State
IL
Country
United States
Zip Code
60637
Yang, Fan; Xu, Jinbo; Zeng, Jianyang (2014) Drug-target interaction prediction by integrating chemical, genomic, functional and pharmacological data. Pac Symp Biocomput :148-59
Wang, Zhiyong; Xu, Jinbo; Shi, Xinghua (2014) Finding alternative expression quantitative trait loci by exploring sparse model space. J Comput Biol 21:385-93
Ma, Jianzhu; Wang, Sheng; Wang, Zhiyong et al. (2014) MRFalign: protein homology detection through alignment of Markov random fields. PLoS Comput Biol 10:e1003500
Wang, Sheng; Ma, Jianzhu; Peng, Jian et al. (2013) Protein structure alignment beyond spatial proximity. Sci Rep 3:1448
Adhikari, Aashish N; Peng, Jian; Wilde, Michael et al. (2012) Modeling large regions in proteins: applications to loops, termini, and folding. Protein Sci 21:107-21
Peng, Jian; Xu, Jinbo (2011) RaptorX: exploiting structure information for protein alignment by statistical inference. Proteins 79 Suppl 10:161-71
Wang, Zhiyong; Zhao, Feng; Peng, Jian et al. (2011) Protein 8-class secondary structure prediction using conditional neural fields. Proteomics 11:3786-92
Wang, Zhiyong; Xu, Jinbo (2011) A conditional random fields method for RNA sequence-structure relationship modeling and conformation sampling. Bioinformatics 27:i102-10
Wang, Sheng; Peng, Jian; Xu, Jinbo (2011) Alignment of distantly related protein structures: algorithm, bound and implications to homology modeling. Bioinformatics 27:2537-45
Peng, Jian; Xu, Jinbo (2011) A multiple-template approach to protein threading. Proteins 79:1930-9