Poster abstracts
Poster number 35 submitted by Jaehoon Yang
The PHF6 (VQIVYK) and related hexapeptides and the formation of Tau protein amyloid
Jaehoon Yang (Department of Chemistry and Biochemistry), Claire Hoffman (Molecular Biophysics Training Program), Mithila Agnihotri, Carol Husby, Jeff Kuret (Department of Biological Chemistry and Pharmacology), Sherwin J. Singer (Department of Chemistry and Biochemistry)
Abstract:
The VQIVYK fragment from the Tau protein, also known as PHF6, is essential for aggregation of Tau into neurofibrillary lesions associated with neurodegenerative diseases. VQIVYK itself forms amyloid fibrils composed of paired β-sheets. Therefore, the full Tau protein and VQIVYK fibrils have been intensively investigated. A central issue in these studies is polymorphism, the ability of a protein to fold into more than one structure. Using all-atom molecular simulations, we generate five stable polymorphs of VQIVYK fibrils, establish their relative free energy with umbrella sampling methods, and identify the side chain interactions that provide stability. The two most stable polymorphs, which have nearly equal free energy, are formed by interdigitation of the mostly hydrophobic VIY ‘‘face’’ sides of the β -sheets. Another stable polymorph is formed by interdigitation of the QVK ‘‘back’’ sides. When we turn to examine structures from cryo-electron microscopy experiments on Tau filaments taken from diseased patients or generated in vitro, we find that the pattern of side chain interactions found in the two most stable face-to-face as well as the back-to-back polymorphs are recapitulated in amyloid structures of the full protein. Thus, our studies suggest that the interactions stabilizing PHF6 fibrils explain the amyloidogenicity of the VQIVYK motif within the full Tau protein and provide justification for the use of VQIVYK fibrils as a test bed for the design of molecules that identify or inhibit amyloid structures.
Our studies of PHF6 revealed the importance of hydrogen-bond chains and π-stacking in stabilizing PHF6 fibrils. As a type of “gain of function” research, we constructed 11 hexapeptides which promised, and indeed we confirmed via simulations, to be even more stable than PHF6. These peptides have been evaluated in experiments, and the speed with which they form fibrils closely correlates with the calculated free energy of association.
Keywords: Molecular Dynamics , Amyloid Fibrils, Free Energy