Molecular Dynamics Simulation of Dimeric and Monomeric Forms of Human Prion Protein Insight.pdf

1176 Biophysical Journal Volume 85 August 2003 1176–1185 Molecular Dynamics Simulation of Dimeric and Monomeric Forms of Human Prion Protein: Insight into Dynamics and Properties Masakazu Sekijima,* Chie Motono,* Satoshi Yamasaki,y Kiyotoshi Kaneko,z and Yutaka Akiyama* *Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology, 2-41-6 Aomi, Koto-ku, Tokyo 135-0064, Japan; yDepartment of Biotechnology, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan; and zDepartment of Cortical Function Disorders, National Institute of Neuroscience, National Center of Neurology and Psychiatry and Japan Science and Technology Corporation, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan ABSTRACT A central theme in prion protein research is the detection of the process that underlies the conformational transition from the normal cellular prion form (PrPC) to its pathogenic isoform (PrPSc). Although the three-dimensional structures of monomeric and dimeric human prion protein (HuPrP) have been revealed by NMR spectroscopy and x-ray crystallography, the process underlying the conformational change from PrPC to PrPSc and the dynamics and functions of PrPC remain unknown. The dimeric form is thought to play an important role in the conformational transition. In this study, we performed molecular dynamics (MD) simulations on monomeric and dimeric HuPrP at 300 K and 500 K for 10 ns to investigate the differences in the properties of the monomer and the dimer from the perspective of dynamic and structural behaviors. Simulations were also undertaken with Asp178Asn and acidic pH, which is known as a disease-associated factor. Our results indicate that the dynamics of the dimer and monomer were similar (e.g., denaturation of helices and elongation of the b-sheet). However, additional secondary struct