The nature of folded states of globular proteins

Abstract

We suggest, using dynamical simulations of a simple heteropolymer modelling the alpha-carbon sequence in a protein, that generically the folded states of globular proteins correspond to statistically well-defined metastable states. This hypothesis, called the metastability hypothesis, states that there are several free energy minima separated by barriers of various heights such that the folded conformations of a polypeptide chain in each of the minima have similar structural characteristics but have different energies from one another. The calculated structural characteristics, such as bond angle and dihedral angle distribution functions, are assumed to arise from only those configurations belonging to a given minimum. The validity of this hypothesis is illustrated by simulations of a continuum model of a heteropolymer whose low temperature state is a well-defined beta-barrel structure. The simulations were done using a molecular dynamics algorithm (referred to as the "noisy" molecular dynamics method) containing both friction and noise terms. It is shown that for this model there are several distinct metastable minima in which the structural features are similar. Several new methods of analyzing fluctuations in structures belonging to two distinct minima are introduced. The most notable one is a dynamic measure of compactness that can in principle provide the time required for maximal compactness to be achieved. The analysis shows that for a given metastable state in which the protein has a well-defined folded structure the transition to a state of higher compactness occurs very slowly, lending credence to the notion that the system encounters a late barrier in the process of folding to the most compact structure. The examination of the fluctuations in the structures near the unfolding----folding transition temperature indicates that the transition state for the unfolding to folding process occurs closer to the folded state.

Multi-basin dynamics of a protein in a crystal environment

“…Fast folding (submillisecond regime) proteins have also been observed [11][12][13][14]. Studies of the protein folding kinetics and stability analyses based on 3D lattice and off-lattice models of polymers with binary interactions (i.e., polar and hydrophobic) that mimic proteins [15][16][17][18][19][20][21] also agree with this picture. Onuchic, Wolynes and collaborators [ 16,[22][23][24] proposed an energy landscape theory of folding with the idea that folding kinetics is best regarded as a progressive organization of an ensemble of partially folded structures, the folding funnel, rather than a serial progression between intermediates.…”

Effect of Finite Size on Cooperativity and Rates of Protein Folding

“…Off-lattice model: We employ coarse-grained off-lattice models for polypeptide chains in which each amino acid is represented using only the C α atoms [21]. Furthermore, we use a Go model [22] in which the interactions between residues forming native contacts are assumed to be attractive and the non-native interactions are repulsive.…”

Funnels, pathways, and the energy landscape of protein folding: A synthesis

“…These substates correspond to slightly different structures found in the population of folded proteins [18]. Evidence for the highest level of this hierarchy has been seen in protein folding simulations [59]. Unfortunately, this issue of energy gaps has been clouded by lattice simulations that have studied the energy spectrum of only the maximally compact states [71,86].…”