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.