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The soul of all living things: Do you know how protein dynamics affect function?
In molecular biology, scientists generally think of proteins as unique structures determined by their amino acid sequence. However, proteins are not static objects but can transition between potentially multiple structural states. These state changes occur on length scales from tens of angstroms to several nanometers and on time scales from nanoseconds to seconds, and these changes are closely linked to functionally relevant phenomena such as allosteric signaling and enzymatic catalysis.
The dynamics of proteins focuses primarily on the transitions between these states, but also involves the properties of the states and their equilibrium populations.
Protein flexibility can be divided into several levels, including local flexibility, regional flexibility and overall flexibility. In terms of local flexibility, parts of a protein structure often deviate from its equilibrium state. Some deviations are harmonious, such as random fluctuations in chemical bonds and bond angles; others are non-harmonious, such as rapid jumps between side chains. NMR spectroscopy is an effective tool for detecting local flexibility.
For example, random coil indices allow the identification of regions of flexibility and possible disorder in proteins. High-resolution electron density maps allow structural biologists to observe flexibility in proteins at room temperature, in contrast to traditional cryogenic freezing techniques.
The frequency distribution and dynamics of flexibility can be obtained through Raman spectroscopy and anisotropic microspectroscopy techniques.
In terms of regional flexibility, many amino acid residues are in close proximity in the protein structure. This applies not only to adjacent residues in the main sequence but also to distant residues that come into contact in the final folded structure. The energy landscapes of these residues are coupled to each other based on various biophysical phenomena, which makes the transitions between their states interconnected. For example, in an α-helix, adjacent residues and amino acids four residues apart also interact with each other, exhibiting coupled allosteric heterogeneity in the structure.
When these coupled residues form pathways connecting functionally important moieties, they may participate in the process of allosteric signaling. For example, when an oxygen molecule binds to one subunit in a hemoglobin tetramer, this information is passed allosterically to the other three subunits, increasing their affinity for oxygen. The flexibility of this coupling is physiologically very useful because it allows rapid loading of oxygen in lung tissue and rapid unloading of oxygen in oxygen-starved tissues such as muscles.
In terms of global flexibility, the presence of multiple domains makes protein networks highly flexible and mobile.
For proteins containing multiple domains, understanding their structural and functional dynamics is critical. For example, ABC transporters, cell motility and motor proteins function in the mutual movement of their domains. By comparing different structures of proteins, scientists can infer domain motions, which can also be observed directly through neutron spin echo spectroscopy measurements.
In enzymes, closure of one domain allows another domain to access the substrate, an induced adaptation that helps reactions proceed in a controlled environment. Scientific research shows that domain movements are critical to the functional dynamics of enzymes, and these movements are often controlled by the side chains of amino acids.
Protein dynamics are not only critical for function but may also facilitate the acquisition of new functions in molecular evolution.
Many studies have shown that flexibility plays a clear role in promoting enzyme catalysis. For example, non-unitary structural dynamics in dihydrofolate reductase allow for greater flexibility in substrate binding. This flexibility means that, because of their structural basis, they may acquire some new functions, which may be further amplified by future mutations. However, biologists are gradually realizing that intrinsically structureless proteins are quite common in eukaryotic genomes, which also poses a challenge to Anfinsen's paradigm.
The conclusion is that the structure of a protein is not only determined by the amino acid sequence, but also affected by its cellular environment, which may make our understanding of protein function deeper and broader. This makes us think about how protein flexibility and evolution jointly shape the diversity and complexity of life.
