3.3 Protein Dynamics and Flexibility: Order and Disorder
in Proteins
Hermann Staudinger concluded his Nobel lecture [1] by saying “macromolecular
chemistry makes use of a number of qualitative correlations: those of shape and of the
associated configurational scope, up to the level of the “atomos” of living substance,
on which the game of Life ensues. In the light of this new knowledge of macromolecular chemistry, the wonder of Life in its chemical aspect is revealed in the
astounding abundance and masterly macromolecular architecture of living matter.”
Thus, he clearly looked at synthetic macromolecules and biopolymers in parallel and
looked for synergies in their understanding [60]. Moreover, self-organization and
dynamics are common aspects in synthetic and biological systems alike [61, 62].
As far as proteins are concerned, the wealth of structural data available today [63]
are from X-ray studies of protein single crystals. However, as stated in an extended
review [64], the occurrence of unstructured regions of significant size (>50 residues)
is surprisingly common in functional proteins. These disordered regions are characterized by great structural flexibility and plasticity. Obvious similarities between
proteins and synthetic polymers are that both classes span a wide range of organization, from completely disordered random coils via molten globules and linked folded
domains to mostly folded crystallizable proteins [64] in the case of biopolymers, and
amorphous via self-organized structures to semicrystalline polymers in the synthetic
case [53]. A reason for the attention being paid to disordered regions of proteins today
is that techniques have recently been developed to analyze their structural propensities in solution by multidimensional NMR and pulsed EPR spectroscopy
[64–68]. These studies of intrinsically disordered proteins (IDPs) or disordered
protein regions indicate that proteins in general have a conformational ensemble of
varying breadth.
As a specific example from our group showing that well-ordered proteins also can
gain significant flexibility, let us consider the functional structure of human serum
albumin (HSA). It is the most abundant protein in human blood plasma and serves as
a transporting agent for various endogenous compounds and drug molecules [69]. Its
capability to bind and transport multiple fatty acids (FA) has been studied extensively
in the past. The research on HSA was severely hampered by the complexity of the
protein and benefited tremendously from crystallographic high-resolution structures.
Nearly 20 years ago, He and Carter reported the first crystal structure [70]. To date, a
plentitude of crystal structures have been deposited in the Protein Data Bank. Even
more important for understanding the binding properties of the protein, however, are
the structures of complexes of HSA and transported molecules, such as fatty acids.
Due to the pioneering work of Curry et al., crystal structures of various HSA–fatty
acid complexes have become accessible [71]. In particular, it was found that fatty
acids are distributed highly asymmetrically in the protein crystal, despite the fact that
HSA itself exhibits a symmetric primary and secondary structure.
In the context of partially disordered proteins, we note that the surface exposed
parts of HSA show a high degree of flexibility, which constitutes a key to the protein’s
304
H.W. Spiess
in Proteins
Hermann Staudinger concluded his Nobel lecture [1] by saying “macromolecular
chemistry makes use of a number of qualitative correlations: those of shape and of the
associated configurational scope, up to the level of the “atomos” of living substance,
on which the game of Life ensues. In the light of this new knowledge of macromolecular chemistry, the wonder of Life in its chemical aspect is revealed in the
astounding abundance and masterly macromolecular architecture of living matter.”
Thus, he clearly looked at synthetic macromolecules and biopolymers in parallel and
looked for synergies in their understanding [60]. Moreover, self-organization and
dynamics are common aspects in synthetic and biological systems alike [61, 62].
As far as proteins are concerned, the wealth of structural data available today [63]
are from X-ray studies of protein single crystals. However, as stated in an extended
review [64], the occurrence of unstructured regions of significant size (>50 residues)
is surprisingly common in functional proteins. These disordered regions are characterized by great structural flexibility and plasticity. Obvious similarities between
proteins and synthetic polymers are that both classes span a wide range of organization, from completely disordered random coils via molten globules and linked folded
domains to mostly folded crystallizable proteins [64] in the case of biopolymers, and
amorphous via self-organized structures to semicrystalline polymers in the synthetic
case [53]. A reason for the attention being paid to disordered regions of proteins today
is that techniques have recently been developed to analyze their structural propensities in solution by multidimensional NMR and pulsed EPR spectroscopy
[64–68]. These studies of intrinsically disordered proteins (IDPs) or disordered
protein regions indicate that proteins in general have a conformational ensemble of
varying breadth.
As a specific example from our group showing that well-ordered proteins also can
gain significant flexibility, let us consider the functional structure of human serum
albumin (HSA). It is the most abundant protein in human blood plasma and serves as
a transporting agent for various endogenous compounds and drug molecules [69]. Its
capability to bind and transport multiple fatty acids (FA) has been studied extensively
in the past. The research on HSA was severely hampered by the complexity of the
protein and benefited tremendously from crystallographic high-resolution structures.
Nearly 20 years ago, He and Carter reported the first crystal structure [70]. To date, a
plentitude of crystal structures have been deposited in the Protein Data Bank. Even
more important for understanding the binding properties of the protein, however, are
the structures of complexes of HSA and transported molecules, such as fatty acids.
Due to the pioneering work of Curry et al., crystal structures of various HSA–fatty
acid complexes have become accessible [71]. In particular, it was found that fatty
acids are distributed highly asymmetrically in the protein crystal, despite the fact that
HSA itself exhibits a symmetric primary and secondary structure.
In the context of partially disordered proteins, we note that the surface exposed
parts of HSA show a high degree of flexibility, which constitutes a key to the protein’s
304
H.W. Spiess