Simulations of kinetically irreversible protein aggregate structure

Abstract

We have simulated the structure of kinetically irreversible protein aggregates in two-dimensional space using a lattice-based Monte-Carlo routine. Our model specifically accounts for the intermolecular interactions between hydrophobic and hydrophilic protein surfaces and a polar solvent. The simulations provide information about the aggregate density, the types of inter-monomer contacts and solvent content within the aggregates, the type and extent of solvent exposed perimeter, and the short- and long-range order all as a function of (i) the extent of monomer hydrophobic surface area and its distribution on the model protein surface and (ii) the magnitude of the hydrophobic-hydrophobic contact energy. An increase in the extent of monomer hydrophobic surface area resulted in increased aggregate densities with concomitant decreased system free energies. These effects are accompanied by increases in the number of hydrophobic-hydrophobic contacts and decreases in the solvent-exposed hydrophobic surface area of the aggregates. Grouping monomer hydrophobic surfaces in a single contiguous stretch resulted in lower aggregate densities and lower short range order. More favorable hydrophobic-hydrophobic contact energies produced structures with higher densities but the number of unfavorable protein-protein contacts was also observed to increase; greater configurational entropy produced the opposite effect. Properties predicted by our model are in good qualitative agreement with available experimental observations.

External Factors Affecting Protein Aggregation

“…263 The ease of aggregate dissolution also depends on the density of protein aggregates. 264 At an intermediate concentration, denaturants can either inhibit or induce protein aggregation because of the formation of partially unfolded states. 198 Urea in the concentration range of 0.5 -2.0 M reduced the amount of HMW Fc fusion protein aggregates formed during elution at pH 3.6 relative to the buffer control.…”

Extent and nature of contacts between protein molecules in crystal lattices and between subunits of protein oligomers

“…This explanation is consistent with simulations of protein crystallization and aggregation that suggest that very strong interactions between proteins are unfavorable toward crystallization and lead to less ordered structures. 54,55 Clearly, both the balance of forces involved (hydrophobic versus polar interactions) and the complementarity of the interfaces (large vs. small patches) appear distinct when comparing oligomer to crystal interfaces. A connection between these two observations can be suggested and provides an alternative explanation for the nonpairwise preferences at crystal interfaces.…”

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.…”