A second molecular biology revolution? The energy landscapes of biomolecular function

The revolution of biology fomented by Watson and Crick, like many others, was powered by ideas imported from abroad. The introduction of the structure–function paradigm that came to dominate twentieth century molecular biology was inspired by the then avant-garde notion from physical chemists and chemical physicists that even living things must conform to the laws of quantum mechanics and structural chemistry. Unlike many others, the molecular biology revolution really worked. Nevertheless, not all the mysteries of life have been conquered by molecular biological imperialists. It has been clear for some time that a new re-structuring of molecular biology, if not a complete revolution, is needed to have a complete picture of life. Newer ideas from physics and chemistry are again being imported into molecular biology. One such powerful idea is the idea of the energy landscape, the realization that biomolecules are not static sculptures but instead are dynamical objects that are always interconverting between a variety of structures with varying energies. Biomolecules must be described statistically not statically. As powerful as are the physicochemical ideas of molecular structure founded on the quantum theory of small molecules, those laws turn out to be insufficient to contain all the possibilities for the immense vital molecules that function in living things. While the main structural themes of biomolecules like the double helix followed from the quantum laws of bonding, how and why one dimensionally connected biomolecules can organize themselves at all in a three-dimensional fashion remained too mysterious since the strong bonding constraints are few in number. Thermal energy is enough to make protein molecules “kick and scream” in the words of Gregorio Weber. Indeed as most strongly emphasized by Frauenfelder (sometimes to the dismay of some doctrinaire structuralists), biomolecules remain incompletely organized and must remain so in order to function.

While it may be simply the visual metaphor of the energy landscape which has captured the imagination of many, it is more important that the landscape concept has not only brought forth new theoretical interpretive tools, computational algorithms and structure prediction schemes, but has also inspired a panoply of new experimental approaches for characterizing the key ensembles in both biomolecular assembly and function. The purpose of this special issue is to display the wide range of biological problems where the landscape way of thinking is now bearing fruit.

The papers in this issue show that energy landscape ideas can help explain a range of biochemical mysteries starting with not only protein folding (‘Equilibrium thermodynamics and folding kinetics of a short, fast-folding, beta-hairpin’ by Camilo A. Jimenez-Cruz and Angel E. Garcia, DOI: 10.1039/c3cp54336f; ‘Effects of Desolvation Barriers and Sidechains on Local-Nonlocal Coupling and Chevron Behaviors in Coarse-Grained Models of Protein Folding’ by Tao Chen and Hue Sun Chan, DOI: 10.1039/c3cp54866j; ‘The Energy Landscape of a Protein Switch’ by Szu-Hua Chen and Ron Elber, DOI: 10.1039/c3cp55209h; ‘Exploring multi-dimensional coordinate-dependent diffusion dynamics on the energy landscape of protein conformation change’ by Zaizhi Lai et al. DOI: 10.1039/c3cp54476a; ‘A hybrid MD-kMC algorithm for folding proteins in explicit solvent’ by Emanuel Karl Peter and Joan-Emma Shea, DOI: 10.1039/c3cp55251a; ‘Diffuse transition state structure for the unfolding of a leucine-rich repeat protein’ by Sadie E. Kelly et al., DOI: 10.1039/c3cp54818j; ‘The kinetics of folding of frataxin’ by Daniela Bonetti et al., DOI: 10.1039/c3cp54055c) but continuing also to the ultimate function of biomolecules, including “disordered ones” (‘The binding mechanisms of intrinsically disordered proteins’ by Jakob Dogan et al., DOI: 10.1039/c3cp54226b; ‘Predicted disorder-to-order transition mutations in IκBα disrupt function’ by Holly Dembinski et al., DOI: 10.1039/c3cp54427c), misfolding (‘Effect of interactions with the chaperonin cavity on protein folding and misfolding’ by Anshul Sirur et al., DOI: 10.1039/c3cp52872c) and chaperone-assisted folding, binding events, binding mechanisms (‘A Kinetic Study of Domain Swapping in Protein’ by Thomas Moschen and Martin Tollinger, DOI: 10.1039/c3cp54126f; ‘Conformational flexibility of loops of myosin enhances global bias in the actin–myosin interaction landscape’ by Qing-Miao Nie et al., DOI: 10.1039/c3cp54464h; ‘NMR Mapping of Protein Conformational Landscapes using Coordinated Behavior of Chemical Shifts upon Ligand Binding’ by Alessandro Cembran et al., DOI: 10.1039/c4cp00110a), receptors (‘Free Energy Landscape of G-Protein Coupled Receptors, Explored by Accelerated Molecular Dynamics’ by Yinglong Miao et al., DOI: 10.1039/c3cp53962h), regulation (‘Protein conformation as a regulator of cell–matrix adhesion’ by Vesa P. Hytönen and Bernhard Wehrle-Haller, DOI: 10.1039/c3cp54884h), allostery and signaling across the cell (‘The free energy landscape in translational science: how can somatic mutations result in constitutive oncogenic activation?’ by Chung-Jung Tsai and Ruth Nussinov, DOI: 10.1039/c3cp54253j). Landscape thinking applies not only to proteins, but to DNA and RNA (‘Sequence-dependent folding landscapes of adenine riboswitch aptamers’ by Jong-Chin Lin et al., DOI: 10.1039/c3cp53932f), protein–RNA interactions (‘Exploring Electrostatic Energy Landscape for Tetraloop-Receptor Docking’ by Zhaojian He et al., DOI: 10.1039/c3cp53655f), and ultimately illuminates how evolution has been shaped by the interrelationship between structure and function (‘From Structure to Function: the Convergence of Structure Based Models and Co-evolutionary Information’ by Biman Jana et al., DOI: 10.1039/c3cp55275f). The basis of all of these papers is that the proper physicochemical description of biological molecules is not as single structures but as conformational ensembles with dynamic distributions of states which change with varying conditions.

The free energy landscape concept has commanded the imagination of many scientists because those who have adopted and exploited it can more deeply grasp mechanisms in biology than what can be achieved by the simple structure, function paradigm. Why has the free energy landscape idea been so useful for portraying function? While X-ray structures capture snapshots from an ensemble, the changes of this ensemble under varying conditions ultimately give rise to the non-linear information flows needed for life. By also depicting the barriers between the active and inactive ensembles of states, the kinetics of information flow in the living cell can begin to be understood. Consider for example a kinase which under normal physiological conditions largely populates its inactive ensemble of substates. Selective binding of an effector such as peptide or protein to conformations transiently found in the active state ensemble will stabilize that ensemble, shifting the population over the barrier toward this state. Free energy landscape ideas clarify how some mutations can be oncogenic: they can either stabilize the active state ensemble or destabilize the inactive state ensemble. Essentially, mutations sculpt the free energy landscape of the kinase and the resulting ensembles of states partner differentially with other elements in the cell to turn on or off regulatory mechanisms.

Collectively, the idea of an eternal but malleable energy landscape of conformational substates has proven to be astonishingly useful.

While conceived originally as a physical concept to describe transitions between protein substates revealed only at cryogenic temperatures and in following years adopted to describe protein folding, its most significant impact will eventually be its application to understanding function. This may be the next revolution in physicochemical biology.

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