Protein dynamics studied by NMR

Williams, R. J. P.

doi:10.1007/bf00185866

Cited by 17 publications

(5 citation statements)

References 29 publications

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“…Within this class of protein an energised nature of the site, X, can be exirernely useful in binding often with fast exchange rates especially if it is forced to be open-sided. A range of examples has been given in reviews [26]. A very fine examplc of the nature of all helical proteins is calmodulin 1271.…”

Section: Generalised Analysis Of Flexible Ligands and Helical Proteinsmentioning

confidence: 99%

Energised (entatic) States of Groups and of Secondary Structures in Proteins and Metalloproteins

Williams¹

1995

European Journal of Biochemistry

252

164

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(Remived 25 luly 199.5) -EJB 9s 122YiOIn this review 1 have examined the fiinctional value of selected states of isolated groups in proteins energised away froni their expected ground states whether they ;ire observed with or without energy perturbation of larger parts of a protein structure. These cnergisations, found in the absence of substrates, are called 'entatic states of groups' [Vallec, B. L. Kr Williams, R. J. P. (1 968) Pn)c-. N~itl Accrcl. S Y . USA 59, 498-5051, A group can be part of an amino acid or any boutid metal ion or ciifitctor. In some particular cases the apoprotein, where the energised metitl ion or cofactor has been removed, or thc protein in which the energised amino acid hns been replaced, has the same back-hone structure a s the holoprotein and even side-chains are only slightly adjusted. This case is quite diffcrent from a condition of a group simultaneously energised with a protein fold, due to their combination, and which thcrefore involves cvnformutional changc in thc protein and the group and which may adjust the group while the protein tightens. The final condition is again stable but retiiovd of the group now niust result in ii reversed protein conformation change. This siinultancous energisation of both the adjustable protein and the gi-o~ip can be local, as in an induced fit or more extensive when it can be likened in sonic cases to 11 retching by rack action, or may involve a change from an almost random to ii structured protein when the group is encrgised in a very Iimitcd way. Thc various energisations must not be confused since they diffelfunctionally. The first can give rise to optimal heightened calitlylic (or other functional) potential 01' the local group but cannot be connected either to cxcitittion of other parts of a protcin as in induced fitting, or to a relay of energy (larger conformational change) in ilie pi-otein. Clearly it rcstricts the rate of exchange of a group. Induced fit can also give rise to group activntion, though to a sonizwhat reduccd degree, while increasing cxchange rate. A dcvicr such as it rack may rather give rise to ii mcchanical activity (message tlansmission), which is relayed ii large distiincc into the protein, and can only give considerably lowcr activation of individual groups but exchange may now be fast. The final citsc involvcs very modest energisation of the g r w p with gross rearrangement and onergisation of the protein ant1 nlay be associated with storage or carrier functions. The groups upon which I concentrate iirc tnetal ions since detaikd electronic and structural knowledge of their ground states are well known, allowing enctgisetl states to he easily detected, but the ideas apply equally to organic side-chains of proteins as will bc shown. A further energisation can arise from the addition of ii substrate to each kind of pmtein. In f:ict all the ideas of energisation applicable to groups having cyclic activity in permanent features of pi-oteiti structure are equally well applied to substrate binding or conversion of substrat...

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Section: Generalised Analysis Of Flexible Ligands and Helical Proteinsmentioning

confidence: 99%

Energised (entatic) States of Groups and of Secondary Structures in Proteins and Metalloproteins

Williams¹

1995

European Journal of Biochemistry

252

164

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“…Dynamic information is necessary. NMR studies may be used to examine the thermal fluctuations about the average structures, and therefore contribute to the characterization of the protein motions. − However, the observed fluctuations are complex superpositions of all atomic motions, and it has not been possible to use such data to reconstruct specific protein motions. As a result, NMR studies are unlikely to contain sufficient information to distinguish between the lock-and-key and induced fit models.…”

Section: Introductionmentioning

confidence: 99%

Flexibility of an Antibody Binding Site Measured with Photon Echo Spectroscopy

2002

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The lock-and-key and induced fit models of antigen binding by antibodies are topics of considerable importance to immunology and protein biochemistry in general. These models ascribe different degrees of flexibility to the antibody combining site and may therefore be distinguished by measuring the response of the protein to the force exerted by charge redistribution and structural reorganization of an optically excited antigen. Spectroscopic characterization of the magnitude and time scale of this protein reorganization is therefore a basis for comparing the flexibility of different antibodies. This approach is used to study a panel of antibodies elicited to the chromophoric antigen 8-methoxypyrene-1,3,6,trisulfonic acid. The reorganization energies of the chromophore-antibody complexes are determined and are found to be distributed over a wide range. Three pulse photon echo peak shift spectroscopy is used to measure the time scales of the reorganization process in one complex. The antibody motions occur on time scales ranging from 75 femtoseconds to 67 picoseconds. Structural origins of the observed protein motions are discussed.

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“…There is no simple relationship between protein flexibility and the average structure, observable by x-ray crystallography (5-7), or necessarily the thermal fluctuations about the average structure as determined by NMR spectroscopy (8)(9)(10). The most pertinent information is available from crystallographic DebyeWaller factors (11) or from NMR order parameters (10).…”

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confidence: 99%

Flexibility and molecular recognition in the immune system

Jimenez

Salazar

Baldridge

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

110

108

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Photon echo spectroscopy has been used to measure the response of three antibody-binding sites to perturbation from electronic excitation of a bound antigen, fluorescein. The three antibodies show motions that range in time scale from tens of femtoseconds to nanoseconds. Relative to the others, one antibody, 4-4-20, possesses a rigid binding site that likely results from a short and inflexible heavy chain complementarity-determining region 3 (HCDR3) loop and a critical Tyr that acts as a ''molecular splint,'' rigidifying the antigen across its most flexible internal degree of freedom. The remaining two antibodies, 34F10 and 40G4, despite being generated against the same antigen, possess binding sites that are considerably more flexible. The more flexible combining sites likely result from longer HCDR3 loops and a deletion in the light chain complementarity-determining region 1 (LCDR1) that removes the critical Tyr residue. The binding site flexibilities may result in varying mechanisms of antigen recognition including lock-and-key, induced-fit, and conformational selection.T he optimization of protein-based molecular recognition may require significant conformational adjustments of the participating proteins, ligands, or substrates. Several models of molecular recognition have been proposed that are differentiated by the role of flexibility. The ''lock-and-key'' model, where no structural optimization of the binding partners is required, presumes that the molecules have a geometry appropriate for tight binding (1). However, there is a growing consensus that protein flexibility may be required for optimal molecular recognition. As a result, two alternatives to the lock-and-key mechanism explicitly consider molecular flexibility. The original model that evoked flexibility, known as ''induced fit,'' posits that after the initial formation of an unoptimized complex, the molecules structurally reorganize to optimize binding interactions (2). A related model, ''conformational selection,'' hypothesizes that a small fraction of molecules exists transiently in appropriate geometries before binding (3). Although induced-fit and conformational selection evoke fluctuations that occur before or after initial complex formation, they both are differentiated from the lock-and-key model by the important role played by protein flexibility. Flexibility may also play an important role in binding specificity, because structurally distinct protein conformations are expected to facilitate the binding of structurally distinct molecules. The importance of flexibility in the affinity and specificity of molecular interactions is nowhere more obvious than in the humoral immune system, where a limited set of proteins (antibodies, Abs) must bind a virtually unlimited range of foreign molecules (i.e., small-molecule antigens, Ags). It has been suggested that the immune system may accomplish this task by using a limited set of flexible Abs that may bind a wide range of Ags (4, 5). Experiments that measure Ab and Ag flexibility would be interes...

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Protein dynamics studied by NMR

Cited by 17 publications

References 29 publications

Energised (entatic) States of Groups and of Secondary Structures in Proteins and Metalloproteins

Energised (entatic) States of Groups and of Secondary Structures in Proteins and Metalloproteins

Flexibility of an Antibody Binding Site Measured with Photon Echo Spectroscopy

Flexibility and molecular recognition in the immune system

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