Alex Morriss-Andrews

Position: Alumni


My work focuses on the development and application of multiscale sampling methods to computer simulation of biomolecules. Currently I am working to improve the free energy convergence of the WExplore [1] enhanced sampling method. We are looking to apply this method to identifying protein binding sites for small molecule ligands. We have collaborated with the Walter Lab at the University of Michigan to identify the dramatic effect of small changes in junction topology to the folding of the hairpin ribozyme RNA. Using the coarse-grained model TOPRNA [2], we discovered a short two-uracil insertion at the junction that significantly improves folding propensity of the unfolded three-way junction hairpin ribozyme construct. This result was confirmed by the Walter lab with single molecule FRET experiments. TOPRNA demonstrates how junction topology alters conformational flexibility of RNA tertiary structure and thus its folding propensity.

My PhD work analyzed the effect of solid surfaces [3,4] and lipid membranes [5] on the aggregation of small peptides using coarse-grained molecular dynamics simulations. While these attractive surfaces increased fibrillar aggregation in general, we observed several key differences between a solid surface and a fluid membrane. Lipids in the membrane coupled to fibril structures, biasing against multi-layered fibrils; conversely, the ordered nature of the fibrils induced a pseudo-crystal structure in the membrane around the peptides, increasing its elastic parameters.

[1] A. Dickson and C.L. Brooks III. "WExplore: Hierarchical Exploration of High-Dimensional Spaces Using the Weighted Ensemble Algorithm", J. Phys. Chem. B, 118 (13), pp 3532–3542 (2014)
[2] A.M. Mustoe, H.M. Al-Hashimi, and C.L. Brooks III. "Coarse Grained Models Reveal Essential Contributions of Topological Constraints to the Conformational Free Energy of RNA Bulges", J. Phys. Chem. B, 118 (10), pp 2615–2627 (2014)
[3] A. Morriss-Andrews, G. Bellesia, and J.-E. Shea. "Effects of surface interactions on peptide aggregate morphology" J. Chem. Phys., 135, 085102 (2011)
[4] A. Morriss-Andrews and J.-E. Shea. "Kinetic pathways to peptide aggregation on surfaces: the effects of beta-sheet propensity and surface attraction", J. Chem. Phys. 136, 065103 (2012)
[5] A. Morriss-Andrews, F.L.H. Brown, and J.-E. Shea. "A Coarse-Grained Model for Peptide Aggregation on a Membrane Surface", J. Phys. Chem. B, 118 (28), pp 8420–8432 (2014)

Funding from the following agencies: