UC San Diego

Protein dynamics takes place on a rugged funnel-like energy landscape that is biased towards the native state. In naturally occurring proteins, this ruggedness caused by non-native interactions is sufficiently smooth (minimally frustrated) that the landscape is dominated by the native interactions. This provides the theoretical foundation for a class of minimalist protein models called structure- based models (SBMs). In the first half of the thesis we develop and characterize an all-atom SBM that seeks to bridge the gulf between coarse-grained SBMs and all-atom empirical models. We report on the robustness of folding mechanisms in the all-atom model and show that the global folding mechanisms in a coarse-grained C[alpha] model and the all-atom model largely agree, although differences can be attributed to geometric heterogeneity in the all-atom model. We then take a careful look at an important aspect of the SBM, the definition of the native contact map, and propose a general algorithm for generating atomically- grained contact maps called "Shadow." We show that this choice of contact map is not only well behaved for protein folding, since it produces consistently cooperative folding behavior in SBMs, but also desirable for exploring the dynamics of macromolecular assemblies since it distributes energy similarly between RNAs and proteins despite their disparate internal packing. All-atom SBMs employing Shadow contact maps provide a general framework for exploring the geometrical features of biomolecules, especially the connections between folding and function. The second half of the thesis explores the intricacies encountered during folding by proteins at two extremes in structural complexity, complicated folds containing knots and simple folds like three-helix bundles. First we map the full free energy landscape of a knotted protein for the first time and show that a native-biased landscape is sufficient to fold complex topologies. We present a folding mechanism generalizable to all known knotted protein topologies : knotting via threading a native-like loop in a pre-ordered intermediate. Lastly, we discuss a simple three-helix bundle structure, whose structural symmetry opens up a "trap-door" to a competing mirror image structure. The simulations suggest that mirror images might not just be a computational annoyance but are competing folds that might switch depending on environmental conditions or functional considerations