[1FT-2] Computation/Information science (1P-28～1P-47)

[1P-37*] Investigating the dissociation process and kinetic rates of DBD-p53/DNA complex by PaCS-MD and MSM

^○Mohamed Marzouk^1,2, Akio Kitao¹ (1.School of Life Science and Technology, Tokyo Institute of Technology, 2.Physics Department, Faculty of Science, Ain Shams University)

The binding of biological molecules plays a crucial role in understanding their function, mechanisms of diseases, and development of drug design.The binding of p53 DNA binding domain(DBD-p53)to DNA is essential for the defensive role of p53 as a guardian of the genome against cancer. Recently, our group used the rare event sampling technique, parallel cascade selection molecular dynamics (PaCS-MD) in combination with Markov state model (MSM) to generate dissociation pathways of MDM2/TAD-p53 complex, then calculated binding free energy and kinetic rates in good agreement with experimental values. However, applying such method for larger systems are still challenging. In this study we generated 75 dissociation pathways of DBD-p53, which binds to a specific sequence of DNA. Then investigated the essential residues during the dissociation. After that, using inter center of mass (inter-COM) distance and vector between DBD-p53 and DNA as reaction coordinates, we built 1D and 3D MSM, respectively, to generate the binding free energy and kinetic rates of the complex. The combination of PaCS-MD/MSM was shown to be useful in investigation of dissociation pathways, calculation of binding energy and kinetic rates of large complex as well.