The first structures of α-synuclein (αSyn) fibrils have recently been solved. Here, we use a unique combination of molecular dynamics simulation strategies to address the minimal nucleation size of the 11-amino acid NAC protofibril solved by X-ray and to interrogate the dynamic behavior of unexpected crystal waters in the steric zipper. We found that protofibrils of >8 chains are thermodynamically stabilized due to protection of the fibril core from solvent influx and ordering of the end strands by the fibril core. In these stable oligomers, water molecules resolved in the crystal structure freely exchange with bulk solvent but are, on average, stably coordinated along the β-sheet by inward-facing Thr72 and Thr75. We confirm the persistence of this water coordination via simulations of the full-length Greek-key structure solved by NMR and speculate that these Thr-water networks are important in the context of enhanced fibril nucleation in the familial A53T mutation.
Bibliographical noteFunding Information:
*Mailing address: Department of Biomedical Engineering, University of Minnesota, 7-105 Hasselmo Hall, 312 Church Street, SE, Minneapolis, MN 55455, USA. E-mail: jnsachs@umn. edu. Telephone: 612-624-7158. Fax: 612-626-6583. ORCID Anthony R. Braun: 0000-0002-9942-3390 Author Contributions T.D.R., A.K.L., and A.R.B. contributed equally to this study. A.K.L. ran REMD simulations and analyses, and T.D.R. ran brute force MD simulations and analyses. J.N.S. and A.G. designed the research. A.R.B., T.D.R., A.K.L., A.G., and J.N.S. wrote the manuscript. Funding This work was supported in part by the National Institutes of Health, Grant R01 NS084998 (to J.N.S.). Notes The authors declare no competing financial interest.
- molecular dynamics