protein dynamics
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Protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providing and , and from one location to another. Proteins differ from one another primarily ...

Protein
s are generally thought to adopt unique structures determined by their
amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, c ...

amino acid
sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these states occur on a variety of length scales (tenths of Å to nm) and time scales (ns to s), and have been linked to functionally relevant phenomena such as
allosteric signaling
allosteric signaling
and enzyme catalysis. The study of protein dynamics is most directly concerned with the transitions between these states, but can also involve the nature and equilibrium populations of the states themselves. These two perspectives— kinetics and
thermodynamics Thermodynamics is a branch of physics that deals with heat, Work (thermodynamics), work, and temperature, and their relation to energy, entropy, and the physical properties of matter and radiation. The behavior of these quantities is governed by ...

thermodynamics
, respectively—can be conceptually synthesized in an "energy landscape" paradigm: highly populated states and the kinetics of transitions between them can be described by the depths of energy wells and the heights of energy barriers, respectively.


Local flexibility: atoms and residues

Portions of protein structures often deviate from the equilibrium state. Some such excursions are
harmonic of a vibrating string are harmonics. A harmonic is any member of the harmonic series (music), harmonic series. The term is employed in various disciplines, including music, physics, acoustics Acoustics is a branch of physics that deals with ...

harmonic
, such as stochastic fluctuations of
chemical bond A chemical bond is a lasting attraction between atom An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any substance that has mass and takes up space by having volume. All everyday ...
s and bond angles. Others are anharmonic, such as sidechains that jump between separate discrete energy minima, or
rotamer In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their composition, structure, properties, behavior and the changes they und ...
s. Evidence for local flexibility is often obtained from protein NMR, NMR spectroscopy. Flexible and potentially disordered regions of a protein can be detected using the random coil index. Flexibility in folded proteins can be identified by analyzing the relaxation (NMR), spin relaxation of individual atoms in the protein. Flexibility can also be observed in very high-resolution electron density maps produced by X-ray crystallography, particularly when diffraction data is collected at room temperature instead of the traditional cryogenic temperature (typically near 100 K). Information on the frequency distribution and dynamics of local protein flexibility can be obtained using Raman and optical Kerr-effect spectroscopy in the terahertz frequency domain.


Regional flexibility: intra-domain multi-residue coupling

Many residues are in close spatial proximity in protein structures. This is true for most residues that are contiguous in the primary sequence, but also for many that are distal in sequence yet are brought into contact in the final folded structure. Because of this proximity, these residue's energy landscapes become coupled based on various biophysical phenomena such as hydrogen bonds, ionic bonds, and van der Waals force, van der Waals interactions (see figure). Transitions between states for such sets of residues therefore become correlated. This is perhaps most obvious for surface-exposed loops, which often shift collectively to adopt different conformations in different crystal structures (see figure). However, coupled conformational heterogeneity is also sometimes evident in secondary structure. For example, consecutive residues and residues offset by 4 in the primary sequence often interact in alpha helix, α helices. Also, residues offset by 2 in the primary sequence point their sidechains toward the same face of beta sheet, β sheets and are close enough to interact sterically, as are residues on adjacent strands of the same beta sheet, β sheet. Some of these conformational changes are induced by post-translational modifications in protein structure, such as phosphorylation and methylation. When these coupled residues form pathways linking functionally important parts of a protein, they may participate in allosteric signaling. For example, when a molecule of oxygen binds to one subunit of the hemoglobin tetramer, that information is allosterically propagated to the other three subunits, thereby enhancing their affinity for oxygen. In this case, the coupled flexibility in hemoglobin allows for cooperative oxygen binding, which is physiologically useful because it allows rapid oxygen loading in lung tissue and rapid oxygen unloading in oxygen-deprived tissues (e.g. muscle).


Global flexibility: multiple domains

The presence of multiple domains in proteins gives rise to a great deal of conformational change, flexibility and mobility, leading to protein domain dynamics. Domain motions can be inferred by comparing different structures of a protein (as in Database of Molecular Motions), or they can be directly observed using spectra measured by neutron spin echo spectroscopy. They can also be suggested by sampling in extensive molecular dynamics trajectories and principal component analysis. Domain motions are important for: * ABC transporters * catalysis * cellular locomotion and motor proteins * formation of protein complexes * ion channels * mechanoreceptors and mechanotransduction * regulatory activity * transport of metabolites across cell membranes One of the largest observed domain motions is the 'swivelling' mechanism in pyruvate phosphate dikinase. The phosphoinositide domain swivels between two states in order to bring a phosphate group from the active site of the nucleotide binding domain to that of the phosphoenolpyruvate/pyruvate domain. The phosphate group is moved over a distance of 45 Å involving a domain motion of about 100 degrees around a single residue. In enzymes, the closure of one domain onto another captures a substrate by an induced fit, allowing the reaction to take place in a controlled way. A detailed analysis by Gerstein led to the classification of two basic types of domain motion; hinge and shear. Only a relatively small portion of the chain, namely the inter-domain linker and side chains undergo significant conformational changes upon domain rearrangement.


Hinges by secondary structures

A study by Hayward found that the termini of α-helices and β-sheets form hinges in a large number of cases. Many hinges were found to involve two secondary structure elements acting like hinges of a door, allowing an opening and closing motion to occur. This can arise when two neighbouring strands within a β-sheet situated in one domain, diverge apart as they join the other domain. The two resulting termini then form the bending regions between the two domains. α-helices that preserve their hydrogen bonding network when bent are found to behave as mechanical hinges, storing `elastic energy' that drives the closure of domains for rapid capture of a substrate.


Helical to extended conformation

The interconversion of helical and extended conformations at the site of a domain boundary is not uncommon. In calmodulin, torsion angles change for five residues in the middle of a domain linking α-helix. The helix is split into two, almost perpendicular, smaller helices separated by four residues of an extended strand.


Shear motions

Shear motions involve a small sliding movement of domain interfaces, controlled by the amino acid side chains within the interface. Proteins displaying shear motions often have a layered architecture: stacking of secondary structures. The interdomain linker has merely the role of keeping the domains in close proximity.


Domain motion and functional dynamics in enzymes

The analysis of the internal dynamics of structurally different, but functionally similar enzymes has highlighted a common relationship between the positioning of the active site and the two principal protein sub-domains. In fact, for several members of the hydrolase superfamily, the catalytic site is located close to the interface separating the two principal quasi-rigid domains. Such positioning appears instrumental for maintaining the precise geometry of the active site, while allowing for an appreciable functionally oriented modulation of the flanking regions resulting from the relative motion of the two sub-domains.


Implications for macromolecular evolution

Evidence suggests that protein dynamics are important for function, e.g. enzyme catalysis in DHFR, yet they are also posited to facilitate the acquisition of new functions by molecular evolution. This argument suggests that proteins have evolved to have stable, mostly unique folded structures, but the unavoidable residual flexibility leads to some degree of functional promiscuity, which can be amplified/harnessed/diverted by subsequent mutations. However, there is growing awareness that intrinsically unstructured proteins are quite prevalent in eukaryotic genomes, casting further doubt on the simplest interpretation of Anfinsen's dogma: "sequence determines structure (singular)". In effect, the new paradigm is characterized by the addition of two caveats: "sequence and cellular environment determine structural ensemble".


References

{{Protein topics Protein folding Protein biosynthesis