Figure 6. The fluctuation curves of numbers of local folding shapes for
PDCD1_MOUSE (red) and PDCD1_HUMAN (blue) proteins. The horizontal axis
is the ruler of sequence, and vertical axis the number of local folding
variations.
Disorder and flexibility in protein
The nature of protein conformation in biological system is not static,
it is flexible following time being and condition change. The process
involves intermediate folding states and stable folding states during
their synthesis and degradation. These protein folding states may have
various half-lifetime, and keep reversible disorder-order transitions.
Also, the intrinsically disordered folds indeed exist in some of
fragments or entire protein.11Dunker AK, Lawson JD, Brown CJ,
Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM,
Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey
RW, Griswold MD, Chiu W, Garner EC, Obradovic Z, ”Intrinsically
disordered protein”. Journal of Molecular Graphics & Modelling. 19
(1): 26–59, (2001).,22Dyson HJ, Wright PE,
”Intrinsically unstructured proteins and their functions”. Nature
Reviews. Molecular Cell Biology. 6 (3): 197–208, (2005)..,33Dunker
AK, Silman I, Uversky VN, Sussman JL, ”Function and structure of
inherently disordered proteins”. Current Opinion in Structural
Biology. 18 (6): 756–64, (2008).
The results from experimental measurement are actually affected by
intrinsically disorder and flexibility in protein. About two-thirds of
data in PDB do not have the complete 3D structures covering entire
sequence by X-ray crystallography measurement because of the unobserved
regions that frequently correspond to the disorder.44Le Gall T,
Romero PR, Cortese MS, Uversky VN,Dunker AK. Intrinsic disorder in the
Protein Data Bank. J Biomol Struct Dyn; 24:325-42, (2007). With
nuclear magnetic resonance (NMR) spectroscopy, it can reveal an ensemble
of protein structures with flexible dynamics or disorder states limited
around a static state. With transmission electron
cryomicroscopy (CryoTEM), it can provide new insights for protein
structure with large assemblies which allow observation of protein
structures in their native environment at cryogenic temperature. With
computational simulations, it can obtain protein dynamics trajectories
which reveal the disorder and flexibility within protein structure. The
protein folding occur in many steps, and it may spend nearly 96% time
in some states, and also in various intermediate states with minimum
thermodynamic free energies in energy landscape.55Heath Ecroyd;
John A. Carver, ”Unraveling the mysteries of protein folding and
misfolding”. IUBMB Life (review). 60 (12): 769–774, (2008). ,66Robert
B Best, ”Atomistic molecular simulations of protein folding”. Current
Opinion in Structural Biology (review). 22 (1): 52–61, (2012).
Under physiological condition, the protein flexibility substantially
plays important role for biological functions. Even after self-assemble
into a native state with active function, some parts of proteins may
remain folding variations.77Berg JM, Tymoczko JL, Stryer
L, ”3.
Protein Structure and Function”. Biochemistry. San Francisco: W. H.
Freeman. ISBN 0-7167-4684-0,
(2002). The protein biological functions associate with either the
native stable structure or the dynamics motion in structure. It is
undeniable that the protein structures with both dynamic disorder
conformations and stable conformations subsequently are linked to
important functions such as allosteric regulation and enzyme
catalysis.88Bu Z, Callaway DJ, ”Proteins move! Protein dynamics
and long-range allostery in cell signaling”. Advances in Protein
Chemistry and Structural Biology. Advances in Protein Chemistry and
Structural Biology. 83: 163–221, (2011).,99Kamerlin
SC, Warshel A, ”At the dawn of the 21st century: Is dynamics the
missing link for understanding enzyme catalysis?”. Proteins. 78 (6):
1339–75, (2010). Although the so-called native conformation is
essential to a specific function in cell, the environmental factors,
ligands and other proteins may cause the native conformation into
altered folds which may trigger to act different biological function,
such as active or inhibiting function or toxic affection. This is actual
process when a drug targets proteins to make the conformation changes
and to cause activation or inhibition for protein function. Overall, a
complete ensemble of conformations really represents the nature of
protein folding for multiple functions in physiological condition or
various environments. It is significant that the PFVM provides the
comprehensive local folding variations for discovery of various
conformations in astronomical number. Of course, the remaining question
is how to distinguish local folding variations in PFVM with association
of function changes. Ultimately, we need better experimental data and
further data mining to understand the role of each local folding
variation in biological functions.
CONCLUSION
The protein structure fingerprint provided a significant means to probe
the protein folding problem, especially overcame the obstacles how to
reveal and handle an astronomical number of folding conformations. The
folding shapes of 5 amino acid residues, as a universal element, are
comprehended, and then expanded over sequence to expose an astronomical
number of folding conformations. A set of 27 PFSC alphabetical letters
are represented as digital expression. The local folding variations in
PFVM really uncovered how the protein folds are correlated by the order
of amino acids in sequence. Also, it provides the prospect to construct
all possible conformations with astronomical number as well as to
predict the most probable conformations for a protein. These advantages
information may promote the research in protein structures, such as the
protein folding, protein structure prediction, intrinsically disordered
protein, protein mutation and protein design etc.