Predicting the Thermodynamic and Structural Properties of Proteins, Peptides and Other Systems

Simulation of the dynamics of solvated proteins or peptides in their native conformation has become essentially routine. The challenge for the future is the study of environmental and concentration dependent phenomena such as protein folding and protein self-assembly under realistic conditions. Critical to our ability to model conformational equilibria is the ability to predict differences in free energies between alternative conformational states and to do this in different environments. The group has simulated the self-association of a small peptide that mimics the action of erythropoietin. This system is a model of protein self-assembly which will be used to investigate crowding and concentration effects. We have also used free energy calculations to investigate the effect of mutation on the stability of the SUC1 protein dimers as a model for protein-protein interactions.

The use of classical molecular dynamics simulations, performed in explicit water, in the refinement of structural models of proteins generated based on either homology or ab-initiois being investigated. Significant improvement in the deviation of the model structures from the experimentally determined structures was observed in a number of cases suggesting that molecular dynamics simulations on a 10's to 100's ns time scale are useful for the refinement of homology models of middle-size proteins, provided the models already have the correct overall fold. However, even if we could routinely simulate on a us timescale, only relatively small structural rearrangements are possible. The conformational free energy surface of a protein is highly convoluted. During folding, proteins easily become trapped forming a wide range of long-lived intermediates. The fact that proteins readily adopt metastable partially folded states is not just a problem for the prediction and refinement of protein structural models; it is also of critical importance in vivo to the overall viability of living cells. For this reason a series of proteins, collectively referred to as molecular chaperones, have evolved with the primary role of assisting the folding of other proteins. We have developed a novel method for the refinement of misfolded protein structures in which the properties of the solvent environment are oscillated in order to mimic some aspects of the role molecular chaperones play in protein folding in vivo. Preliminary results show that this very simple approach can be used to promote large scale structural rearrangements and promote folding in simulations. For example in figure 3 we show the refinement of an ab-initio structural model of the protein 1sro. In this case the protein was placed within a spherical cage and the interaction between the cage and the protein varied as a function of time, mimicking the action of the chaperone. As can readily be seen, the refinement protocol has led to a significant improvement in the overall fold, a much greater improvement than observed in control simulations performed without the cage.

The thermodynamic properties of proteins and peptides are dominated by their environment, in particular, the properties of water which can behave very differently when in bulk or when in a restricted environment. In a very elegant series of studies the group has investigated the properties of water in confined spaces. We have been able to show that a monolayer of water between two surfaces can freeze even at room temperature. Furthermore, we have shown that the temperature of freezing is highly dependent on the local electric field. This not only has applications in material science and in understanding adhesion between surfaces but also opens the question of whether water at protein-protein interfaces may have long-range order.

This page was last updated on July the 10th, 2017.

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