Effects of All-Atom and Coarse-Grained Molecular Mechanics\nForce Fields on Amyloid Peptide Assembly: The Case of a Tau K18 Monomer

To\npropose new mechanism-based therapeutics for Alzheimer’s\ndisease (AD), it is crucial to study the kinetics and oligomerization/aggregation\nmechanisms of the hallmark tau proteins, which have various isoforms\nand are intrinsically disordered. In this study, multiple all-atom\n(AA) and coarse-grained (CG) force fields (FFs) have been benchmarked\non molecular dynamics (MD) simulations of K18 tau (M243–E372),\nwhich is a truncated form (130 residues) of full-length tau (441 residues).\nFF19SB is first excluded because the dynamics are too slow, and the\nconformations are too stable. All other benchmarked AAFFs (Charmm36m,\nFF14SB, Gromos54A7, and OPLS-AA) and CGFFs (Martini3 and Sirah2.0)\nexhibit a trend of shrinking K18 tau into compact structures with\nthe radius of gyration (ROG) around 2.0 nm, which is much smaller\nthan the experimental value of 3.8 nm, within 200 ns of AA-MD or 2000\nns of CG-MD. Gromos54A7, OPLS-AA, and Martini3 shrink much faster\nthan the other FFs. To perform meaningful postanalysis of various\nproperties, we propose a strategy of selecting snapshots with 2.5 <\nROG < 4.5 nm, instead of using all sampled snapshots. The calculated\nchemical shifts of all C, CA, and CB atoms have very good and close\nroot-mean-square error (RMSE) values, while Charmm36m and Sirah2.0\nexhibit better chemical shifts of N than other FFs. Comparing the\ncalculated distributions of the distance between the CA atoms of CYS291\nand CYS322 with the results of the FRET experiment demonstrates that\nCharmm36m is a perfect match with the experiment while other FFs exhibit\nlimitations. In summary, Charmm36m is recommended as the best AAFF,\nand Sirah2.0 is recommended as an excellent CGFF for simulating tau\nK18.