Competition between protein folding and aggregation: A three-dimensional lattice-model simulation

Abstract

Aggregation of protein molecules resulting in the loss of biological activity and the formation of insoluble deposits represents a serious problem for the biotechnology and pharmaceutical industries and in medicine. Considerable experimental and theoretical efforts are being made in order to improve our understanding of, and ability to control, the process. In the present work, we describe a Monte Carlo study of a multichain system of coarse-grained model proteins akin to lattice models developed for simulations of protein folding. The model is designed to examine the competition between intramolecular interactions leading to the native protein structure, and intermolecular association, resulting in the formation of aggregates of misfolded chains. Interactions between the segments are described by a variation of the Go potential [N. Go and H. Abe, Biopolymers 20, 1013 (1981)] that extends the recognition between attracting types of segments to pairs on distinct chains. For the particular model we adopt, the global free energy minimum of a pair of protein molecules corresponds to a dimer of native proteins. When three or more molecules interact, clusters of misfolded chains can be more stable than aggregates of native folds. A considerable fraction of native structure, however, is preserved in these cases. Rates of conformational changes rapidly decrease with the size of the protein cluster. Within the timescale accessible to computer simulations, the folding-aggregation balance is strongly affected by kinetic considerations. Both the native form and aggregates can persist in metastable states, even if conditions such as temperature or concentration favor a transition to an alternative form. Refolding yield can be affected by the presence of an additional polymer species mimicking the function of a molecular chaperone.

Phase behavior of a lattice protein model

“…This may well explain why, to our knowledge, no such simulation has been reported thus far ͑see, however, Bratko et al 25 and Smith et al, 26 where they, respectively, simulate 6 and 4 proteins but using a bidimensional lattice 8,27,28 or a intermediate resolution model͒. Our multiprotein model exhibits three phases: vapor, liquid, and crystal.…”

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

“…Given current computational capabilities, simpler models are required to simulate multiprotein systems. Computer simulations using low-resolution models, which are based on a coarse-grained representation of protein geometry and energetics, have been used by a few investigators to study protein aggregation [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] Although such models provide invaluable insights into the basic physics underlying protein aggregation in general, they do not adequately account for the different forces, such as hydrogen bonding, that play an important role in fibril formation.…”

Effect of rate of chemical or thermal renaturation on refolding and aggregation of a simple lattice protein

“…There have been several Monte Carlo or exact enumeration studies of the aggregation of low-resolution protein models aimed at answering some of the basic questions regarding the competition between protein folding and aggregation (Bratko and Blanch, 2001;Broglia et al, 1998;Giugliarelli et al, 2000;Harrison et al, 1999Harrison et al, , 2001Istrail et al, 1999;Przybycien, 1994a, 1994b;Toma and Toma, 2000). Most studies were limited to only a few chains, which is not enough to fully understand the competition between folding and aggregation in a multichain system.…”