Paper Info
Title
Uncovering the Dominant Motion Modes of Allosteric Regulation Improves Allosteric Site Prediction
Abstract
Allostery is an important mechanism that biological systems use to regulate function at a distant site. Allosteric drugs have attracted much attention in recent years due to their high specificity and the possibility of overcoming existing drug-resistant mutations. However, the discovery of allosteric drugs remains challenging as allosteric regulation mechanisms are not clearly understood and allosteric sites cannot be accurately predicted. In this study, we analyzed the dominant modes that determine motion correlations between allosteric and orthosteric sites using the Gaussian network model and found that motion correlations between allosteric and orthosteric sites are dominated by either fast or slow vibrational modes. This dependence of modes results from the relative locations of the two sites and local secondary structures. Based on these analyses, we developed CorrSite2.0 to predict allosteric sites by taking the maximum of the Z-scores calculated from using either slow or fast modes. The prediction accuracy of CorrSite2.0 outperformed other commonly used allosteric site prediction methods with prediction accuracy over 90.0%. Our study uncovers the relationship of protein structure, dynamics, and allosteric regulation and demonstrates that using the dominant motion modes greatly improves allosteric site prediction accuracy. CorrSite2.0 has been integrated into the CavityPlus web server, which can be accessed at http://www.pkumdl.cn/cavityplus. CorrSite2.0 provides a powerful and user-friendly tool for allosteric drug and protein design.
Year
DOI
Venue
2022
10.1021/acs.jcim.1c01267
JOURNAL OF CHEMICAL INFORMATION AND MODELING
DocType
Volume
Issue
Journal
62
1
ISSN
Citations 
PageRank 
1549-9596
1
0.35
References 
Authors
0
5
Name
Order
Citations
PageRank
Juan Xie110.35
Shiwei Wang210.35
Youjun Xu3202.58
Minghua Deng410.35
Luhua Lai536933.78