Solvent–amino acid interaction energies in 3-D-lattice MC simulations of model proteins. Aggregation thermodynamics and kinetics

Recently, we devised an energy scale to vary systematically amino acid–solvent interactions for Monte Carlo simulations of lattice model proteins in water. For 27-mer and 64-mer protein chains, changes in the interaction energies produce quite different protein-folding behavior. Here, for two- to six-chain systems, we investigate the effect of interaction parameters and chain length on protein aggregation. Here too, small changes in the interaction energies produce different classes of protein behavior: non-aggregating; reversibly aggregating; irreversibly aggregating while maintaining part or all of the native structure. Interaction parameters optimized for fast folding and high cooperativity in single-chain simulations provide the least aggregation in multi-chain simulations. Simulations with 27-mers and with 64-mers suggest that the interaction-energy parameters optimal for stability against aggregation depend only weakly on protein size. Although we are not able to find an energy parameter set for 27-mers that makes the native, non-aggregating state the most stable state, we have obtained such a set of parameters for 64-mers, indicating a strong influence of chain length on aggregation properties.

[1]  N. Go.  Theoretical studies of protein folding. , 1983, Annual review of biophysics and bioengineering.

[2]  R. Jernigan,et al.  Estimation of effective interresidue contact energies from protein crystal structures: quasi-chemical approximation , 1985 .

[3]  K. Dill,et al.  A lattice statistical mechanics model of the conformational and sequence spaces of proteins , 1989 .

[4]  H. G. Petersen,et al.  Error estimates on averages of correlated data , 1989 .

[5]  J. King,et al.  Protein Folding Intermediates and Inclusion Body Formation. , 1989, Bio/Technology.

[6]  S. Prusiner,et al.  Molecular biology of prion diseases , 1991, Science.

[7]  P. J. Phillips,et al.  The Science of Polymer Molecules: Contents , 1993 .

[8]  R J Fletterick,et al.  Structural clues to prion replication. , 1994, Science.

[9]  S. Prusiner,et al.  Prion diseases and neurodegeneration. , 1994, Annual review of neuroscience.

[10]  P. J. Phillips,et al.  The Science of Polymer Molecules: Contents , 1994 .

[11]  R. Wetzel.  Mutations and off-pathway aggregation of proteins. , 1994, Trends in biotechnology.

[12]  R. Jaenicke.  Folding and Association Versus Misfolding and Aggregation of Proteins , 1995 .

[13]  A. Klibanov,et al.  Aggregation of a Lyophilized Pharmaceutical Protein, Recombinant Human Albumin: Effect of Moisture and Stabilization by Excipients , 1995, Bio/Technology.

[14]  Charles F. Zukoski,et al.  Protein interactions and crystallization , 1996 .

[15]  R. Wetzel.  For Protein Misassembly, It's the “I” Decade , 1996, Cell.

[16]  M. Oliveberg,et al.  Transient aggregates in protein folding are easily mistaken for folding intermediates. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[17]  A. Fink.  Protein aggregation: folding aggregates, inclusion bodies and amyloid. , 1998, Folding & design.

[18]  P. Gupta,et al.  Effect of denaturant and protein concentrations upon protein refolding and aggregation: A simple lattice model , 1998, Protein science : a publication of the Protein Society.

[19]  R. Broglia,et al.  Folding and aggregation of designed proteins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[20]  A. Chakraborty,et al.  Random heteropolymer adsorption on disordered multifunctional surfaces: Effect of specific intersegment interactions , 1998 .

[21]  G. Benedek,et al.  Oligomerization and phase separation in globular protein solutions. , 1998, Biophysical chemistry.

[22]  F. Cohen,et al.  Thermodynamics of model prions and its implications for the problem of prion protein folding. , 1999, Journal of molecular biology.

[23]  M. Hecht,et al.  De novo amyloid proteins from designed combinatorial libraries. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[24]  V. Pande,et al.  Dynamic lattice Monte Carlo simulation of a model protein at an oil/water interface , 2000 .

[25]  A. Maritan,et al.  Compactness, aggregation, and prionlike behavior of protein: A lattice model study , 2000 .

[26]  D. Bratko,et al.  Competition between protein folding and aggregation: A three-dimensional lattice-model simulation , 2001 .

[27]  David Eisenberg,et al.  A domain-swapped RNase A dimer with implications for amyloid formation , 2001, Nature Structural Biology.

[28]  Gordon M. Crippen,et al.  Lattice models of protein folding permitting disordered native states , 2002 .

[29]  D. Thirumalai,et al.  Exploring protein aggregation and self‐propagation using lattice models: Phase diagram and kinetics , 2002, Protein science : a publication of the Protein Society.

[30]  3D-Lattice Monte Carlo simulations of model proteins. Size effects on folding thermodynamics and kinetics. , 2003, Biophysical chemistry.

[31]  D. Bratko,et al.  Effect of secondary structure on protein aggregation: A replica exchange simulation study , 2003 .