Abstract
Protein folding is a multi-micro second time scale event and involves many conformational transitions. Crucial conformational transitions responsible for biological functions of biomolecules are difficult to capture using current state-of-the-art molecular dynamics (MD) simulations. Protein folding, being a stochastic process, witnesses these transitions as rare events. Many new methodologies have been proposed for observing these rare events. In this work, a temperature-aided cascade MD is proposed as a technique for studying the conformational transitions. Folding studies for Engrailed homeodomain and Immunoglobulin domain B of protein A have been carried out. Using this methodology, the unfolded structures with RMSD of 20 Å were folded to a structure with RMSD of 2 Å. Three sets of cascade MD runs were carried out using implicit solvation, explicit solvation, and charge updation scheme. In the charge updation scheme, charges based on the conformation obtained are calculated and are updated in the topology file. In all the simulations, the structure of 2 Å was reached within a few nanoseconds using these methods. Umbrella sampling has been performed using snapshots from the temperature-aided cascade MD simulation trajectory to build an entire conformational transition pathway. The advantage of the method is that the possible pathways for a particular reaction can be explored within a short duration of simulation time and the disadvantage is that the knowledge of the start and end state is required. The charge updation scheme adds the polarization effects in the force fields. This improves the electrostatic interaction among the atoms, which may help the protein to fold faster.
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Acknowledgments
The authors gratefully acknowledge the Department of Electronics and Information Technology (DeitY), Government of India, New Delhi, for providing financial support. This work was performed using the “Bioinformatics Resources and Applications Facility (BRAF)” and “National PARAM Supercomputing Facility (NPSF)” at C-DAC, Pune.
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Supplementary Table 1 denotes the numbering of the atoms of each of the amino acids. This table can be used to refer the atom types against the atom numbers. The charge fluctuation for these atom numbers have been plotted for all the residues of the both the proteins in Supplementary Figs. 1 and 2. Population Distribution plot for umbrella sampling simulations are provided as Supplementary Fig. 3. Detailed PCA on individual trajectories have been provided. The advantages and disadvantages of the three different treatment employed in the parallel cascade MD simulations have been discussed in Supplementary Table 2 (DOCX 3297 kb)
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Jani, V., Sonavane, U. & Joshi, R. Traversing the folding pathway of proteins using temperature-aided cascade molecular dynamics with conformation-dependent charges. Eur Biophys J 45, 463–482 (2016). https://doi.org/10.1007/s00249-016-1115-4
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DOI: https://doi.org/10.1007/s00249-016-1115-4