We review our joint experimental-theoretical effort on the folding of photo-switchable -helices. The folding kinetics of these peptides is profoundly non-exponential, which is attributed to a partitioning of the unfolded state into several misfolded traps. These traps are connected to the folded state in a hub-like fashion with folding barriers of different heights. Molecular dynamics simulatio...

The equilibrium unfolding of the Formin binding protein 28 (FBP) WW domain, a stable three-stranded beta-sheet protein, can be described as reversible apparent two-state folding. Kinetics studied by laser temperature jump reveal a third state at temperatures below the midpoint of unfolding. The FBP free-energy surface can be tuned between three-state and two-state kinetics by changing the tempe...

We present a new approach to study a multitude of folding pathways and different folding mechanisms for the 20-residue mini-protein Trp-Cage using the combined power of replica exchange molecular dynamics (REMD) simulations for conformational sampling, transition path theory (TPT) for constructing folding pathways, and stochastic simulations for sampling the pathways in a high dimensional struc...

In the last couple of years, there has been increasing debate as to the presence and role of intermediate states on the folding pathways of several small proteins, including the 76-residue protein ubiquitin. Here, we present detailed kinetic studies to establish whether an intermediate state is ever populated during the folding of this protein. We show that the differences observed in previous ...

Experimental observations suggest that proteins follow different folding pathways under different environmental conditions. We perform molecular dynamics simulations of a model of the c-Crk SH3 domain over a broad range of temperatures, and identify distinct pathways in the folding transition. We determine the kinetic partition temperature-the temperature for which the c-Crk SH3 domain undergoe...

Protein structures in nature often exhibit a high degree of regularity (secondary structures, tertiary symmetries, etc.) absent in random compact conformations. We demonstrate in a simple lattice model of protein folding that structural regularities are related to high designability and evolutionary stability. We measure the designability of each compact structure by the number of sequences whi...

The physical basis of two-state-like folding transitions and the tremendous diversity in folding rates is elucidated by directly simulating the folding kinetics of 52 representative proteins. Relative to the results from a common modeling approach, the diversity of the simulated folding rates can be increased from ~10(2.1) to the experimental ~10(6.0) by a modest decrease in the spatial range o...

Reaching a ground state of a spin system is analogous to a protein evolving into its native state. We study the “folding” times for various random Ising spin systems and determine characteristic temperatures that relate to the “folding”. Under optimal kinetic conditions, the “folding” times scale with the system size as a power law with a non-universal exponent. This is similar to what happens ...

GroEL is an allosteric protein that facilitates protein folding in an ATP-dependent manner. Herein, the relationship between cooperative ATP binding by GroEL and the kinetics of GroE-assisted folding of two substrates with different GroES dependence, mouse dihydrofolate reductase (mDHFR) and mitochondrial malate dehydrogenase, is examined by using cooperativity mutants of GroEL. Strong intra-ri...

We propose a general theory to describe the distribution of protein-folding transition paths. We show that transition paths follow a predictable sequence of high-free-energy transient states that are separated by free-energy barriers. Each transient state corresponds to the assembly of one or more discrete, cooperative units, which are determined directly from the native structure. We show that...