Protein-DNA recognition is a central biological process that governs the life of cells. A protein will often undergo a conformational transition to form the functional complex with its target DNA. The protein conformational dynamics are expected to contribute to the stability and specificity of DNA recognition and therefore may control the functional activity of the protein-DNA complex. Understanding how the conformational dynamics influences the protein-DNA recognition is still challenging. Here, we developed a two-basin structure-based model to explore functional dynamics in Sulfolobus solfataricus DNA Y-family polymerase IV (DPO4) during its binding to DNA. With explicit consideration of non-specific and specific interactions between DPO4 and DNA, we found that DPO4-DNA recognition is comprised of first 3D diffusion, then a short-range adjustment sliding on DNA and finally specific binding. Interestingly, we found that DPO4 is under a conformational equilibrium between multiple states during the binding process and the distributions of the conformations vary at different binding stages. By modulating the strength of the electrostatic interactions, the flexibility of the linker, and the conformational dynamics in DPO4, we drew a clear picture on how DPO4 dynamically regulates the DNA recognition. We argue that the unique features of flexibility and conformational dynamics in DPO4-DNA recognition have direct implications for low-fidelity translesion DNA synthesis, most of which is found to be accomplished by the Y-family DNA polymerases. Our results help complete the description of the DNA synthesis process for the Y-family polymerases. Furthermore, the methods developed here can be widely applied for future investigations on how various proteins recognize and bind specific DNA substrates.
Protein-DNA recognition is crucial for many key biological processes in cells. Protein often undergoes large-scale conformational change during DNA recognition. However, the physical and global understanding of flexible protein-DNA binding is still challenging. Here, we developed a theoretical approach to investigate binding of a Y-family DNA polymerase to its target DNA during the DNA synthesis process. The results of electrostatic-controlled multi-step DNA binding process accompanied with multi-state conformational transition of protein occurring throughout are in remarkable agreement with experiments. During the process of protein-DNA recognition, the flexibility is found to facilitate both the conformational transition of protein (intra-chain dynamics) and DNA binding (inter-chain dynamics) simultaneously. Therefore, we provided a quantitative description of protein-DNA binding mechanism that flexibility or conformational change regulates DNA recognition dynamically, leading to high efficiency and specificity of function for protein-DNA recognition.
Citation:Chu X, Liu F, Maxwell BA, Wang Y, Suo Z, et al. (2014) Dynamic Conformational Change Regulates the Protein-DNA Recognition: An Investigation on Binding of a Y-Family Polymerase to Its Target DNA. PLoS Comput Biol 10(9): e1003804. doi:10.1371/journal.pcbi.1003804
Editor:Alexander Donald MacKerell, University of Maryland, Baltimore, United States of AmericaReceived: May 5, 2014; Accepted: July 10, 2014; Published: September 4, 2014
Copyright: © 2014 Chu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.
Funding: XC and FL acknowledge support from the National Science Foundation of China (Grants 21190040, 11174105 and 91227114) and 973 project of China (2010CB933600). ZS is supported by an National Science Foundation Grant (MCB-0960961) of USA. BAM was supported by a Presidential Fellowship at The Ohio State University. JW thanks National Science Foundation for support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.