Beyond the Protein Landscape

Protein landscapes in which conformational transition states separate "open (inactive)" and "closed (active)" forms of enzymes and other molecule machines doubtless represent an important conceptual framework. This special topic identifies groundbreaking ways to permeate the iconic graphical cartoons of protein landscapes with quantitative structural and kinetic details necessary to elevate understanding of enzyme catalytic, allosteric, and chemical free energy transduction mechanisms including the regulatory interactions of intrinsically disordered proteins. Computational methods are developing quickly and offer the opportunity for conceptual experiments. Magnetic resonance spin relaxation methods potentially offer time-dependent measurement of coupling between the motions of atoms high energy states in an enzyme that are otherwise invisible and over timescales on which motions ranging from bond rotations (fs–ps) to domain motions (ms–hours). However, a range of obstacles limits the realization of their promise. Interpreting relaxation data requires appropriate MD simulations (1) whose dimensionality also must be reduced (2,3). Specific structural barriers that present at conformational transition states need to be identified (4) and tested by combinatorial mutagenesis experiments to capture the energetics of coupled motions before and after transition states; (5-7). Structural states along the free energy landscape can be put in sequence only by appropriate rate measurements. Single molecule studies, time-resolved spectroscopy, crystallography and cryoEM will are weighing in with some concrete examples. The kinetic asymmetry that couples various forms of chemical free energy into directed motion by motors (8), enzymes, and molecular machines in general (9) requires molecular gating mechanisms that need to be identified and described in generally applicable terms. The formation of the right questions to be asked about how to connect structure, dynamics and function is now paramount.

Guest Editors: Charlie Carter and George Phillips