title: Multiscale Modeling for Protein/Peptide Complexes

Jonathon B Ferrell (TALK)

institution: University of Vermont

abstract:

The study of large protein complexes at the all-atom level is computationally challenging. While the use of coarse-grain models provide a promising solution to this problem; the lack of model details often leads to limitations in real applications. In order to resolve this dilemma, we propose the use of multi-resolution methods. A multi-resolution method enables us to begin with a fully or partially coarse-grained model for speed and performance, thus sampling a larger conformational space and quickly converging to the region of interest. Finally, we can switch to an all-atom model for structure refinement at high accuracy. To demonstrate proof-of-concept, we have successfully utilized this methodology for peptide aggregation; by gradually moving from coarse grain (MARTINI), to all atom coarse grain (AACG), and finally to all atom. Our results show an excellent balance between computational efficiency and model accuracy, compared to prior experiments and all-atom simulations.

To further develop this multiscale methodology, we focus on the innovation of systematically designed, coarser-grained force fields. Towards this end, we are constructing a machine learning (ML) algorithm to explore new avenues to create these force fields. With preliminary success, we show that this approach bears a potentially substantial impact on advancing our capacity to model and study larger, more complex biochemical/biophysical systems.

References:

1. Liao, C.; Zhao, X.; Schneebeli, S. T.; Shelley, J.; Li, J.* “Capturing the Multiscale Dynamics of Membrane Protein Complexes with All-Atom, Mixed-Resolution, and Coarse-Grained Models” Phys. Chem. Chem. Phys. 2017, 19, 9181.

2. Shelley, M.; Selvan, M. E.; Zhao, J.; Babin, V.; Liao, C.; Li, J.; Shelley, J. “A New Mixed All-Atom/Coarse-Grained Model for Peptides: Application to Melittin Aggregation in Aqueous Solution” J. Chem. Theory Comput. 2017, 13, 3881.

3. Zhao, X.; Liao, C.; McCarthy, D.; Ferrell, J. B.; Li, J.* “A Top-Down Multiscale Approach to Simulate Peptide Aggregation” 2018, Submitted to Phys. Chem. Chem. Phys.