| The peptide binding on protein plays an important role in innate immunity and signaling pathways, relevant to some common diseases such as cancer and tumour. The theoretical study of protein-peptide interactions can provide information at molecular level to help understand the details of these complex biological processes, in order to regulate the protein-peptide interactions and assist the treatments of the related diseases. In addition, investigating the protein-peptide docking process can help design novel peptide drugs.The peptide flexibility causes the computational difficulty when using the conventional docking tools. Here, we are going to propose a flexible docking approach to exam the docking of C1-CATH2 on the interface of TLR4-MD2. This approach contains the following steps:1) Homology modeling and ab initio modeling to obtain a series of candidate a-helix structures.2) Each a-helix is used as the initial structure to generate 3600 conformations using ZDock, leading to the top 600 conformations with favorable scores.3) The top 600 conformations were subject to RosettaDock redock plus consensus scoring for generating the best conformation.4) The RosettaDock semi-flexible docking was used to optimize the starting structure.5) Energy minimization was performed using amber to further optimize the structure.6) The peptide fragment was grown gradually to the full peptide using our inhouse tools and Amber minimization. Molecular dynamics simulations and binding free energy analysis were used to determine the accuracy and stability of the docked conformations. Finally, according to the binding free energy, van der Waals, electrostatic interactions and so on, four possible modes have been obtained for the TLR4-MD2/C1-CATH2 binding.This article provides a comprehensive flexible peptide growth approach for the study of the proteins-peptides docking process. It is efficient, practicable and helpful to the research of protein-peptide interactions. |
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