How native state topology affects the folding of Dihydrofolate Reductase and Interleukin-1beta

The overall structure of the transition state and intermediate ensembles experimentally observed for Dihydrofolate Reductase and Interleukin-1beta can be obtained utilizing simplified models which have almost no energetic frustration. The predictive power of these models suggest that, even for these very large proteins with completely different folding mechanisms and functions, real protein sequences are sufficiently well designed and much of the structural heterogeneity observed in the intermediates and the transition state ensembles is determined by topological effects.Comment: Proc. Natl. Acad. Sci. USA, in press (11 pages, 4 color PS figures) Higher resolution PS files can be found at http://www-physics.ucsd.edu/~cecilia/pub_list.htm

Funnels in Energy Landscapes

Local minima and the saddle points separating them in the energy landscape are known to dominate the dynamics of biopolymer folding. Here we introduce a notion of a "folding funnel" that is concisely defined in terms of energy minima and saddle points, while at the same time conforming to a notion of a "folding funnel" as it is discussed in the protein folding literature.Comment: 6 pages, 3 figures, submitted to European Conference on Complex Systems 200

Folding Kinetics of Protein Like Heteropolymers

Using a simple three-dimensional lattice copolymer model and Monte Carlo dynamics, we study the collapse and folding of protein-like heteropolymers. The polymers are 27 monomers long and consist of two monomer types. Although these chains are too long for exhaustive enumeration of all conformations, it is possible to enumerate all the maximally compact conformations, which are 3x3x3 cubes. This allows us to select sequences that have a unique global minimum. We then explore the kinetics of collapse and folding and examine what features determine the various rates. The folding time has a plateau over a broad range of temperatures and diverges at both high and low temperatures. The folding time depends on sequence and is related to the amount of energetic frustration in the native state. The collapse times of the chains are sequence independent and are a few orders of magnitude faster than the folding times, indicating a two-phase folding process. Below a certain temperature the chains exhibit glass-like behavior, characterized by a slowing down of time scales and loss of self-averaging behavior. We explicitly define the glass transition temperature (Tg), and by comparing it to the folding temperature (Tf), we find two classes of sequences: good folders with Tf > Tg and non-folders with Tf < Tg.Comment: 23 pages (plus 10 figures included in a seperate file) LaTeX, no local report nu

Kinetic and thermodynamic analysis of proteinlike heteropolymers: Monte Carlo histogram technique

Using Monte Carlo dynamics and the Monte Carlo Histogram Method, the simple three-dimensional 27 monomer lattice copolymer is examined in depth. The thermodynamic properties of various sequences are examined contrasting the behavior of good and poor folding sequences. The good (fast folding) sequences have sharp well-defined thermodynamic transitions while the slow folding sequences have broad ones. We find two independent transitions: a collapse transition to compact states and a folding transition from compact states to the native state. The collapse transition is second order-like, while folding is first order. The system is also studied as a function of the energy parameters. In particular, as the average energetic drive toward compactness is reduced, the two transitions approach each other. At zero average drive, collapse and folding occur almost simultaneously; i.e., the chain collapses directly into the native state. At a specific value of this energy drive the folding temperature falls below the glass point, indicating that the chain is now trapped in local minimum. By varying one parameter in this simple model, we obtain a diverse array of behaviors which may be useful in understanding the different folding properties of various proteins.Comment: LaTeX, 16 pages, figures in separate uufile. Requires psfig.sty Minor revision, fixed typo in preprint number (no other changes

Thermodynamics and Kinetics of Folding of a Small Peptide

We study the thermodynamics and kinetics of folding for a small peptide. Our data rely on Monte Carlo simulations where the interactions among all atoms are taken into account. Monte Carlo kinetics is used to study folding of the peptide at suitable temperatures. The results of these canonical simulations are compared with that of a generalized-ensemble simulation. Our work demonstrates that concepts of folding which were developed in the past for minimalist models hold also for this peptide when simulated with an all-atom force field

Diffusive Dynamics of the Reaction Coordinate for Protein Folding Funnels

The quantitative description of model protein folding kinetics using a diffusive collective reaction coordinate is examined. Direct folding kinetics, diffusional coefficients and free energy profiles are determined from Monte Carlo simulations of a 27-mer, 3 letter code lattice model, which corresponds roughly to a small helical protein. Analytic folding calculations, using simple diffusive rate theory, agree extremely well with the full simulation results. Folding in this system is best seen as a diffusive, funnel-like process.Comment: LaTeX 12 pages, figures include