Deconstructing the native state: energy landscapes, function, and dynamics of globular proteins.

Proteins are highly complex molecules with features exquisitely selected by nature to carry out essential biological functions. Physical chemistry and polymer physics provide us with the tools needed to make sense of this complexity. Upon translation, many proteins fold to a thermodynamically stable form known as the native state. The native state is not static, but consists of a hierarchy of conformations, that are continuously explored through dynamics. In this review we provide a brief introduction to some of the core concepts required in the discussion of the protein native dynamics using energy landscapes ideas. We first discuss recent works which have challenged the structure-function paradigm by demonstrating function in disordered proteins. Next we examine the hierarchical organization in the energy landscapes using atomistic molecular dynamics simulations and principal component analysis. In particular, the role of direct and water-mediated contacts in sculpting the landscape is elaborated. Another approach to studying the native state ensemble is based on choosing high-resolution order parameters for computing one- or two-dimensional free energy surfaces. We demonstrate that 2D free energy surfaces provide rich thermodynamic and kinetic information about the native state ensemble. Brownian dynamics simulations on such a surface indicate that protein conformational dynamics is weakly activated. Finally, we briefly discuss implicit and coarse-grained protein models and emphasize the solvent role in determining native state structure and dynamics.

Hierarchical organization of eglin c native state dynamics is shaped by competing direct and water-mediated interactions.

The native state dynamics of the small globular serine protease inhibitor eglin c has been studied in a long 336 ns computer simulation in explicit solvent. We have elucidated the energy landscape explored during the course of the simulation by using Principal Component Analysis. We observe several basins in the energy landscape in which the system lingers for extended periods. Through an iterative process we have generated a tree-like hierarchy of states describing the observed dynamics. We observe a range of divergent contact types including salt bridges, hydrogen bonds, hydrophilic interactions, and hydrophobic interactions, pointing to the frustration between competing interactions. Additionally, we find evidence of competing water-mediated interactions. Divergence in water-mediated interactions may be found to supplement existing direct contacts, but they are also found to be independent of such changes. Water-mediated contacts facilitate interactions between residues of like charge as observed in the simulation. Our results provide insight into the complexity of the dynamic native state of a globular protein and directly probe the residual frustration in the native state.