An effective environmental force constant is introduced to quantify the molecular resilience (or its opposite, “softness”) of a protein structure and relate it to biological function and activity. Specific resilience-function relations were found in neutron-scattering experiments on purple membranes containing bacteriorhodopsin, the light-activated proton pump of halobacteria; the connection between resilience and stability is illustrated by a study of myoglobin in different environments. Important advantages of the neutron method are that it can characterize the dynamics of any type of biological sample—which need not be crystalline or monodisperse—and that it enables researchers to focus on the dynamics of specific parts of a complex structure with deuterium labeling.

/pdf/how-soft-is-a-protein-a-protein-dynamics-force-constant-4ldrmeu5nn.pdf

How Soft Is a Protein? A Protein Dynamics Force Constant Measured by Neutron Scattering

Protein motions are essential for function. Comparing protein processes with the dielectric fluctuations of the surrounding solvent shows that they fall into two classes: nonslaved and slaved. Nonslaved processes are independent of the solvent motions; their rates are determined by the protein conformation and vibrational dynamics. Slaved processes are tightly coupled to the solvent; their rates have approximately the same temperature dependence as the rate of the solvent fluctuations, but they are smaller. Because the temperature dependence is determined by the activation enthalpy, we propose that the solvent is responsible for the activation enthalpy, whereas the protein and the hydration shell control the activation entropy through the energy landscape. Bond formation is the prototype of nonslaved processes; opening and closing of channels are quintessential slaved motions. The prevalence of slaved motions highlights the importance of the environment in cells and membranes for the function of proteins.

/pdf/slaving-solvent-fluctuations-dominate-protein-dynamics-and-a54izekfcn.pdf

Slaving: Solvent fluctuations dominate protein dynamics and functions

A molecular dynamics simulation of myoglobin provides the first direct demonstration that the potential energy surface of a protein is characterized by a large number of thermally accessible minima in the neighborhood of the native structure (for example, approximately 2000 minima were sampled in a 300-picosecond trajectory). This is expected to have important consequences for the interpretation of the activity of transport proteins and enzymes. Different minima correspond to changes in the relative orientation of the helices coupled with side-chain rearrangements that preserve the close packing of the protein interior. The conformational space sampled by the simulation is similar to that found in the evolutionary development of the globins. Glasslike behavior is expected at low temperatures. The minima obtained from the trajectory do not satisfy certain criteria for ultrametricity.

http://science.sciencemag.org/content/sci/235/4786/318.full.pdf

Multiple Conformational States of Proteins: A Molecular Dynamics Analysis of Myoglobin

The concept that proteins exist in numerous different conformations or conformational substates, described by an energy landscape, is now accepted, but the dynamics is incompletely explored. We have previously shown that large-scale protein motions, such as the exit of a ligand from the protein interior, follow the dielectric fluctuations in the bulk solvent. Here, we demonstrate, by using mean-square displacements (msd) from Mossbauer and neutron-scattering experiments, that fluctuations in the hydration shell control fast fluctuations in the protein. We call the first type solvent-slaved or α-fluctuations and the second type hydration-shell-coupled or β-fluctuations. Solvent-slaved motions are similar to the α-fluctuations in glasses. Their temperature dependence can be approximated by a Vogel-Tammann-Fulcher relation and they are absent in a solid environment. Hydration-shell-coupled fluctuations are similar to the β-relaxation in glasses. They can be approximated by a Ferry or an Arrhenius relation, are much reduced or absent in dehydrated proteins, and occur in hydrated proteins even if embedded in a solid. They can be responsible for internal processes such as the migration of ligands within myoglobin. The existence of two functionally important fluctuations in proteins, one slaved to bulk motions and the other coupled to hydration-shell fluctuations, implies that the environment can control protein functions through different avenues and that no real protein transition occurs at ≈200 K. The large number of conformational substates is essential; proteins cannot function without this reservoir of entropy, which resides mainly in the hydration shell.

Bulk-solvent and hydration-shell fluctuations, similar to α- and β-fluctuations in glasses, control protein motions and functions

The binding of dioxygen and carbon monoxide to heme proteins such as myoglobin and hemoglobin has been studied with flash photolysis. At temperatures below 200 K, binding occurs from within the heme pocket and, contrary to expectation, with nearly equal rates for both ligands. This observation has led to a reexamination of the theory of the association reaction taking into account friction, protein structure, and the nature of electronic transitions. The rate coefficients for the limiting cases of large and small friction are found with simple arguments that use characteristic lengths and times. The arguments indicate how transition state theory as well as calculations based on nonadiabatic perturbation theory, which is called the Golden Rule, may fail. For ligand-binding reactions the data suggest the existence of intermediate states not directly observed so far. The general considerations may also apply to other biomolecular processes such as electron transport.

https://science.sciencemag.org/content/sci/229/4711/337.full.pdf

D. Kucheida

Papers

Protein dynamics. Mössbauer spectroscopy on deoxymyoglobin crystals.