Local conformational flexibility

A model for initial DNA lesion recognition by NER and MMR based on local conformational flexibility. DNA Repair, 4, 455-464. 

RJ. Isaacs and H.P. Spielmann, A Model for Initial DNA Lesion Recognition by NER and MMR Based on Local Conformational Flexibility , DNA Repair, 2004,3,455... 

It should be noted that the method for incorporating local conformational flexibility into the calculations of pH-dependent protein properties, described by Alexov and Gunner" (see below), can be also considered as partially treating the problem of tautomers. 

The main advantage of NMR spectroscopy is its use with proteins in solution. In consequence, rather than obtaining a single three-dimensional structure of the protein, the final result for an NMR structure is a set of more or less overlying structures which fulfill the criteria and constraints given particularly by the NOEs. Typically, flexibly oriented protein loops appear as largely diverging structures in this part of the protein. Likewise, two distinct local conformations of the protein are represented by two differentiated populations of NMR structures. Conformational dynamics are observable on different time scales. The rates of equilibration of two (or more) substructures can be calculated from analysis of the line shape of the resonances and from spin relaxation times Tj and T2, respectively. 

M. Rholam and P. Nicolas, Conformational flexibility of neurophysin as investigated by local motions of fluorophores. Relationships with neurohypophyseal hormone binding,... 

Before doing so, we briefly examine the influence of conformation and flexibility. Indeed, formation of succinimide is limited in proteins due to conformational constraints, such that the optimal value of the and ip angles (Sect. 6.1.2) around the aspartic acid and asparagine residues should be +120° and -120°, respectively [99], These constraints often interfere with the reactivity of aspartic acid residues in proteins, but they can be alleviated to some extent by local backbone flexibility when it allows the reacting groups to approach each other and, so, favors the intramolecular reactions depicted in Fig. 6.27. When compared to the same sequence in more-flexible random coils, elements of well-formed secondary structure, especially a-helices and 13-turns, markedly reduce the rate of succinimide formation and other intramolecular reactions [90][100],... 

One of the most intriguing recent examples of disordered structure is in tomato bushy stunt virus (Harrison et ah, 1978), where at least 33 N-terminal residues from subunit types A and B, and probably an additional 50 or 60 N-terminal residues from all three subunit types (as judged from the molecular weight), project into the central cavity of the virus particle and are completely invisible in the electron density map, as is the RNA inside. Neutron scattering (Chauvin et ah, 1978) shows an inner shell of protein separated from the main coat by a 30-A shell containing mainly RNA. The most likely presumption is that the N-terminal arms interact with the RNA, probably in a quite definite local conformation, but that they are flexibly hinged and can take up many different orientations relative to the 180 subunits forming the outer shell of the virus particle. The disorder of the arms is a necessary condition for their specific interaction with the RNA, which cannot pack with the icosahedral symmetry of the protein coat subunits. 

An important extension to rigid-body fitting is the so-called directed tweak technique [105]. Directed tweak allows for an RMS fit, simultaneously considering the molecular flexibility. By the use of local coordinates for the handling of rotatable bonds, it is possible to formulate analytical derivatives of the objective function. With a gradient-based local optimizer flexible RMS fits are obtained extremely fast. However, no torsional preferences may be introduced. Therefore, directed tweak may result in energetically unfavorable conformations. 

The important difference between linear and cyclic peptides is the reduced conformational flexibility imposed by the cyclization. 14,151 Cyclic peptides have, therefore, been under intense investigation with respect to their conformational preferences 30,31 and their different turn motifs, e.g. reverse turns. 32 35 To differentiate between the structural influences of the numerous sequence elements the following special concepts have been described 161 (1) Global constraints are structural characteristics that restrict the whole molecule, e.g. the macrocyclic structure of the peptide framework and (2) local constraints comprise a large number of structure-inducing building blocks, such as proline, D-amino acids, and turn mimetics. 

Several methods have been developed for the incorporation of thioamide bonds at defined positions into linear peptides (for details see Vol. E 22c, Section 10.9.1) 498,499 The resulting linear precursors can be cyclized by standard procedures, although the thioamide bond should not be located in penultimate position, since activation of the carboxy group leads to thia-zolone formation as outlined in Scheme 31.1500-502 The cyclization yield of thioamide-containing peptides is generally rather low. This effect results from the additional local steric restrictions exerted by the thioamide bond, which leads to decreased conformational flexibility 488 ... 

It has been found out that the structure of proteins is flexible and there are many differences between the static spatial image of a protein and a dynamic view of its structure. This divergence is caused by the fact that the repetitive part of a-helices and [3-strands of protein folds, often described as a succession of secondary structures, can assume different local spatial orientation. Two experimental methods can be used to measure the flexibility in precise regions of protein structures (the anatomic mean square displacement, B-factor, measured during crystallographic experiments, and indirectly by NMR experiments which show different local conformation that could correspond directly to different stages of protein structures) (Bornot et al., 2007). 

Fields, P.A., and G.N. Somero (1998). Hot spots in cold adaptation Localized increases in conformational flexibility in lactate dehydrogenase A4 orthologs of Antarctic notothe-nioid fishes. Proc. Natl. Acad. Sci. USA. 95 11476-11481. 

The influence of methyl groups in the 3-position on the epoxidation of Z or E double bonds in highly flexible macrocycles has been discussed in terms of local conformers 138,172. This concept has been shown to be useful for the rough estimation of diastereoselectivities, where complete conformational analysis is laborious however, attempts to localize relative energies of transition states by MM2 calculations of the corresponding alkenes and epoxides strongly underestimate torsional interactions, the parameters utilized for epoxides have moreover, meanwhile been revised114. 

One of the major problems of the theory of intramolecular local mobility or kinetic flexibility lies in the establishment of the principal mechanism of mobility for the macromolecules of a given chemical structure and constitution and of local conformational microstructure. The question arises, which of the elementary acts leads to the ability of individual parts of the macromolecule for changing their shape during definite time intervals characteristic of a certain class of motions 38-148)... 

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