Folding abnormalities of the triple helix have been demonstrated in collagen diseases such as osteogenesis imperfecta in which the mutation leads to the substitution of a single Gly in the (Gly-X-Y)n sequence pattern by a larger residue. Model peptides can be used to clarify the details of normal collagen folding and the consequences of the interruption of that folding by a Gly substitution. NM...

Minding your p's and q's has become as important to protein-folding theorists as it is for those being instructed in the rules of etiquette. To assess the quality of structural reaction coordinates in predicting the transition-state ensemble (TSE) of protein folding, we benchmarked the accuracy of four structural reaction coordinates against the kinetic measure P(fold), whose value of 0.50 defi...

The endoplasmic reticulum (ER) is a well-orchestrated protein-folding machine composed of protein chaperones, proteins that catalyze protein folding, and sensors that detect the presence of misfolded or unfolded proteins. A sensitive surveillance mechanism exists to prevent misfolded proteins from transiting the secretory pathway and ensures that persistently misfolded proteins are directed tow...

The concept of a funneled energy landscape and the principle of minimal frustration are the theoretical foundation justifying the applicability of structure-based models. In simulations, a protein is commonly reduced to a CR-bead representation. These simulations are sufficient to predict the geometrical features of the folding mechanism observed experimentally utilizing a concise formulation o...

Introduction One of the greatest challenges in modern structural biology is to understand how a newly formed polypeptide sequence finds its correct and unique fold. Real progress has been made towards establishing a fundamental and universal mechanism by which protein folding takes place, and such advances have come from the combination of experimental and theoretical techniques. In our laborat...

Recent theoretical/computational studies based on simplified protein models and experimental investigation have suggested that the native structure of a protein plays a primary role in determining the folding rate and mechanism of relatively small single-domain proteins. Here, we extend the study of the relationship between protein topology and folding mechanism to a larger protein with complex...

A microscopic study of functional disorder-order folding transitions coupled to binding is performed for the p27 protein, which derives a kinetic advantage from the intrinsically disordered unbound form on binding with the phosphorylated cyclin A-cyclin-dependent kinase 2 (Cdk2) complex. Hierarchy of structural loss during p27 coupled unfolding and unbinding is simulated by using high-temperatu...

We investigate the folding of a 125-bead heteropolymer model for proteins subject to Monte Carlo dynamics on a simple cubic lattice. Detailed study of a few sequences revealed a folding mechanism consisting of a rapid collapse followed by a slow search for a stable core that served as the transition state for folding to a near-native intermediate. Rearrangement from the intermediate to the nati...

Molecular dynamics simulations hold the promise of providing an atomic-level description of protein folding that cannot easily be obtained from experiments. Here, we examine the extent to which the molecular mechanics force field used in such simulations might influence the observed folding pathways. To that end, we performed equilibrium simulations of a fast-folding variant of the villin headp...

Molecular chaperones are known to be essential for avoiding protein aggregation in vivo, but it is still unclear how they affect protein folding mechanisms. We use single-molecule Förster resonance energy transfer to follow the folding of a protein inside the GroEL/GroES chaperonin cavity over a time range from milliseconds to hours. Our results show that confinement in the chaperonin decelerat...