Conformational change in Protein

    1. Overview
    2. Selection of Proteins to illustrate Conformational changes
    3. General References
    4. Internet links

Overview of conformational changes

Protein conformation is of paramount importance in understanding biomolecular interactions. In the simplest scenario, two molecules may interact with no change in their conformation, as in the key-and-lock model. Molecular interactions that involve conformational changes in the interacting molecules are more versatile. In the induced-fit model, two molecules bind optimally with each other only after conformational changes at their interface. Conformational changes may also take place away from the binding interface. This is often the prerequisite for functional activity. For protein like haemoglobin that shows allosteric behaviour, the binding of small molecules at a region of the protein affects its binding affinity with other molecules at a distant region. In membrane receptors binding of ligand at the extracellular region causes changes at the cytoplasmic region, so that an extracellular signal is allowed to alter intracellular activity.

Conformational changes in proteins are made possible by their intrinsic flexibility. These changes may occur with only relatively small expenditure of energy. At the molecular structural level, conformational changes in single polypeptides are the result of changes in main chain torsional angles and side chain orientations. The overall effect of such changes may be localised with reorientations of a few residues and small torsional changes in the regional main chain. On the other hand torsional changes localised at very few critically placed residues may lead to large changes in tertiary structure. The later type of conformational changes is described as domain motions.

Domain motions

Domain motions have two basic components. Hinge motions may occur within strands, beta-sheets and alpha-helices not constrained by tertiary packing forces. To qualify as fulcrum for hinge-motion, residue must bear very little tertiary structure packing constraints on its main chain. The hinge lies outside the interface between the two domains inter-connected by the hinge. On hinge-opening the motion is perpendicular to the plane of the interface, which is lost after opening. The closed conformation is usually stabilised by a bound ligand. This is necessarily so, for if the closed conformation is strongly held together without a ligand, then the hinge opening will have to cross a high energy barrier. Shear motions occur parallel to the interface between closely packed segments of polypeptides. This type of motion is more severely constrained with additional packing contacts due to interdigitating side chains. A large enough sheared domain motion is due to the combination of a number of shear movements. Proteins that shear often have layered architecture, with shearing that may occur across helix-helix, helix-sheet, helix-loop and sheet-loop interfaces. Helix-helix shearing is the predominant type, usually between crossed helices with interhelical angles of 600-900.

Hinged-motion occurs in the context of secondary structure interactions. Hinge motion at extended strand involves a few large changes in main chain torsion angles at the hinge connecting two domains, constrained only by the Ramachandran allowance of torsional angles. As the range of (phi, psi) angles is relatively large for extended strand, the hinge angle can change by up to 600 with only torsional changes in two residues. In beta-sheets two adjacent strands can move like hinges of a door, with extra constraint of hydrogen bonds that hold the sheet together. To obtain the same hinge angular change, torsional changes at three or more residues are required. Alpha helices are further constrained with their more restrictive hydrogen bonding, thereby in need of more small-amplitude torsional angular changes to bend themselves significantly. Proline-kinked helix may alow larger torsional angular changes. Torsional angular changes may stretch an alpha helix by about 3 Angstroms into a 310 helix. There are also cases where a long helix may split into two smaller helices inter-connected by a short extended strand that was previously in helical conformation.

Shear-motion occurs in the context of tertiary structure interactions. Large shear movement that make the interdigitating lock from one state to another is not observed in domain motions, as in subunit interface of allosteric proteins. On the other hand small shear movements that do not require interdigitational repacking are common in domain motions. These shear movements are accommodated by small changes in side chain torsional angles with no significant deformation in main chain torsional configuration of the interface segments. As a consequence the shear-motion causes the segments to shift and rotate relative to each other for up to 2 Angstroms and 150 , respectively.

Allosteric transitions

Multimeric proteins have an extra dimensioality to conformational transitions due to their quarternary structure. Haemoglobin is the classic prototype of allosteric proteins with cooperative behaviour. In the case of lamprey haemoglobulin, cooperativity is mediated by reversible dissociation and association of subunits. Packing at subunit interfaces are broken off all together. As for human haemoglobin this is achieved by equilibrium between two alternative quarternary structures of the tetramer. The overall structure changes are due to breaking and formation of electrostatic interactions at the tertiary and quaternary levels, as a result of binding to oxygen or other allosteric effectors. At the interface there is large shear motion that involves repacking in transition between tense and relax states. Cooperativity can also be realised singularly by saving expenditure of entropic energy, as in the binding of dimeric trp repressor and immunoglobulins to operator and antigen, respectively. After binding of one monomer to a binding site on the target molecule with energy expenditure to pay for the decrease in entropy, the binding of the other monomer to adjacent binding site on the same ligand molecule requires less energy for entropy reduction because the first binding has juxtapose the two interacting molecules, such that the second monomer is already placed in the favourable position to interact with the second binding site without having to increase the order of the bimolecular complexity much more.


  1. Perutz MF. Mechanisms of cooperativity and allosteric regulation in proteins. Quarterly Review of Biophysics 22:139-236, 1989
  2. Gerstein M, Lesk AM, Chothia C. Structural Mechanisms for Domain Movements in Proteins. Biochemistry 33:6739-6749, 1994.
  3. Janin J, Wodak SJ. Structural Domains in Proteins and their Role in the Dynamics of Protein Function. Prog Biophys molec Biol 42:21-78, 1983.

Links for further information

Acknowledgment: The molecular models presented in this hypertext is created using R Sayle's Raswin Molecular Graphics Window version 2.6.

Email author: CM Vun

Last modified 25th Nov 1996.