Protein Conformation

At the tertiary structural level, most protein molecules are able to shift reversibly between several different but related stable conformations and are known as allosteric proteins. Such proteins may be able to form several alternative sets of hydrogen bonds, disulfide bridges and Van der Waals forces of about equal energy among their constituent amino acid side chains. Each alternative set of intraprotein bonds and charge distribution requires a change in the spatial relationships between components of the polypeptide chains and thus motion occurs among the states. Only certain distinct conformations are energetically favorable and any intermediate conformations are unstable and unlikely. Charge redistribution (i.e. dipole oscillation) can also couple to conformational switching. Thus step-like, nonlinear jumping occurs between specific conformations so that only a discrete number of alternative conformations exist for a given protein, and random switching from conformation to conformation is limited.

Figure 6.2: Alpha helix with three "spines" formed by hydrogen bonds (dashed lines) between hydrogen and oxygen atoms. With permission from Bolterauer, Henkel and Opper (1986).

Each distinct conformation of an allosteric protein has a different surface and a different ability to interact with other binding molecules or "ligands." Only one of several conformations may have a high affinity for a particular ligand and the presence or absence of that ligand can determine the conformation that the protein adopts. Two distinct ligands may bind specifically to different surfaces of the same protein, so that the concentration of one ligand may change the affinity of the protein for the other. Such allosteric mechanisms facilitate fine tuning and regulation of many biological processes in which proteins transduce, or integrate various modes of signaling and information. Allosteric proteins are especially effective signaling devices when they exist as aggregates of identical subunits. The conformation of one subunit can influence that of neighboring subunits, producing a collective effect similar to amplification or switching in a computer. The collective behavior of hemoglobin in its binding of oxygen is one example; state transformations in microtubules may be another.

The conformational state of a specific protein is regulated by a variety of factors and may have profound importance for functional activity. Hemoglobin is an iron containing protein in red blood cells which carries oxygen from the lungs to the various body tissues like brain, heart, or muscle. Hemoglobin which binds an oxygen molecule is in a different conformation ("oxyhemoglobin") than hemoglobin without oxygen ("deoxyhemoglobin"). The conformational state of hemoglobin found inside red blood cells determines the protein's capacity to bind or release oxygen. Hemoglobin conformation is determined by factors which include the availability of oxygen, temperature, pH, presence of certain other molecules (i.e. 2,3 DPG), and the amount of nearby oxyhemoglobin. The latter describes a "collective" effect; when a critical amount of hemoglobin binds oxygen, the oxyhemoglobin conformation is easier to attain for the remaining protein molecules. This results in a "sigmoid" shape to the curve which describes oxygen/hemoglobin binding. The nature of this collective phenomenon is an indication of the behavior of protein assemblies.

Different frequencies of conformational changes coexist cooperatively in the same protein (Table 6.1). Some totally reversible conformations like oxyhemoglobin persist for tens of seconds; others can be very short-lived (i.e. femtoseconds: 10-15 seconds), or very long (minutes to hours). The oxyhemoglobin conformation persists until the oxygen molecule is delivered to the tissue whose mitochondria use it to produce ATP and GTP. To reach their binding sites within hemoglobin's central core, oxygen molecules diffuse through transient packing defects in the protein's structure. Nanosecond scale, conformational "breathing" permits the oxygen molecules to slip in and out, dependent on surrounding pH, temperature, hormones and other factors. There thus appear to be at least two levels of conformational states in hemoglobin. The "functional" conformation (binding vs no binding of oxygen) are relatively long lasting (long enough to carry oxygen from the lungs to tissue for delivery). In addition there are more rapid conformational vibrations such as the nanosecond "breathing" which facilitates diffusion of oxygen molecules through hemoglobin to reach their binding sites.

Amplitude of motions

0.001 nanometer to 10 nanometers


0.1 kilocalories to 100 kilocalories

Time Range

10-15 sec (femtosecond) to 103 sec (many minutes)

Time for collective, functional steps

10-9 sec (nanoseconds)

Types of motion

local atom fluctuations

side chain oscillations

displacements of loops, arms, helices, domains and subunits

collective elastic body modes, coupled atom fluctuations, solitons and other nonlinear motions, coherent excitations

Table 6-1: Protein Conformational Dynamics—Motions of Globular Proteins at Physiological Temperature (Modified from Karplus and McCammon, 1984).

Table 6-1: Protein Conformational Dynamics—Motions of Globular Proteins at Physiological Temperature (Modified from Karplus and McCammon, 1984).

The vast majority of processes of biological interest are in the time scale greater than one nanosecond, which also lies in the collective mode realm for protein dynamics (Karplus and McCammon, 1984). Protein conformational changes in the nanosecond time frame are able to be coupled to a stimulus and result in a functional conformational change. Three fundamental features appear to control these functional states: hydrophobic interactions, charge redistribution and hydrogen bonding. Appropriate stimuli including neurotransmitters, voltage alterations, hormones, ions like calcium, and enzyme substrates can induce conformational changes within specific proteins. Conformational transduction is the sensitive link in the mechanism of anesthetic gas molecules (Chapter 7) and indicates that cognitive functions relating to consciousness depend in some way on protein conformational regulation. In many cases, proteins "integrate" a number of factors to result in a new conformation (Figure 6.3). Portions of proteins may be dynamically active with functional importance. For example, electron transfer processes such as that which occur in the mitochondrial production of ATP may rely on vibrational coupling and fluctuations which alter the distances between electron donors and acceptors. Relative motions of distinct structural domains within proteins are important in their activities related to muscle contraction, enzyme activities, antibody functions, and assembly and activities of supra-molecular structures such as viruses and cytoskeletal proteins. Dynamic conformational changes of proteins are the dynamics of living organisms.

Figure 6.3: Protein switching between two different conformational states induced by binding of ligand, calcium ion, or voltage change. One mechanism proposed by Fröhlich is that dipole oscillations (e) within hydrophobic regions of proteins may be a trigger, or switch for the entire protein.
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