Sylvie Furois-Corbin

A possible model for the inner wall of the acetylcholine receptor channel

A structural model of the inner wall of the acetylcholine receptor (AChR) channel is developed using assumptions derived from the results of the recent labelling experiments of the MII helices by noncompetitive blockers. The assumption of steric blocking of the channel by chlorpromazine (CPZ) in the neighbourhood of the labelled serines imposes the MII helices to be in contact at this level and allows the calculation of their minimal interaxial distance. The assumption that CPZ diffuses to this position through the upper crowded part of the channel imposes that the helices are more distant in this region and permits the determination of a tilt of about 7 degrees with respect to the central axis. Electrostatic potentials are used to demonstrate the effect of the charged residues at the exit of the pore. A discussion is given on the possible aptitude of MI to satisfy the contacts necessary with the MII/s at the different heights of the model.

Theoretical study of the packing of α-helices by energy minimization: effect of the length of the helices on the packing energy and on the optimal configuration of a pair

Abstract Energy optimizations carried out on systems formed by two equivalent (L-Ala)n α-helices of increasing length, from n = 6 to 26, show that the two α-helices pack in a nearly antiparallel fashion and very close together, satisfying roughly the “knobs into holes” concept, and that the maximum interaction energy increases regularly with increasing n. From n = 14 upwards the arrangements obtained for all the complexes are similar due to the effect of “non-bonded” interactions becoming prevalent over the “dipole-dipole” interactions. Below this length such a regularity is not observed due to the importance of end effects.

Thoeretical study of the packing of α-helices of poly(l-alanine) into transmembrane bundles. Possible significance for ion-transfer

Abstract Energy optimizations are carried out on packages of N α -helices of poly( l -alanine) from N = 3−7, starting from an initial arrangement of the helices at the vertices of various polygonal prisms, in view of the possible formation of channel-making bundles in membranes. The results show: that, for each N , a number of stable packages exist; that the presence of one pair (and even two) of adjacent parallel helices in a package is not incompatible with its stability, due to the overcompensation of its unfavorable electrostatic energy by the sum of the corresponding favorable terms for the antiparallel pairs; and that some packages provide ready-made pores in their interior. The energy profile computed for Na + inside one of the pores (resulting from five helices) shows a favorable energy all the way through, in spite of the methyl groups protruding into the channel. Similarly one water molecule interacts favorably with this pore throughout.

Energy profiles in the acetylcholine receptor (AChR) channel. The MII-helix model and the role of the remaining helices.

It is demonstrated by theoretical computations that no favorable energy profile for cation transfer can be obtained in a model of the AChR channel constructed with the sole five MII helices of the inner wall. A favorable profile is obtained upon including the effect of the remaining helices of the five subunits. The decisive role, for the exit of the ion, of the charged residues situated at the N‐terminal of the MII segments, established before, is underlined further. The role of the other elements of the channel wall (peptide carbonyl oxygens, hydrocarbon residues and polar side chains) is analyzed.

Conformation and pairing properties of the N-terminal fragments of trichorzianine and alamethicin: a theoretical study

Energy optimizations are carried out on the N-terminal fragment of trichorzianine in comparison to that of alamethicin. The results indicate that the helical character of the (Ac...Pro13) sequence of trichorzianine (TA IIIc) is essentially alpha with a bend in the helix axis in the end proline region, a structure comparable to the optimal alpha-helical structure of the corresponding segment (Ac...Pro14) of alamethicin AI. However, two weak n----n + 3 interactions coexist in trichorzianine with the alpha-helical n----n + 4 hydrogen bonds. The possible role of the glutamine side-chains in pairing such segments together is considered.

Theoretical Study of Potential Ion-Channels formed by a Bundle of alpha-Helices: Effect of the Presence of Polar Residues along the Channel Inner Wall

In a channel-forming bundle of five alpha-helices of poly-L-alanine, the replacement of all the alanyl side-chains lining the inner wall by serines is shown, by energy optimization, to produce only small modifications of the packing. The stability of the bundle is larger than that of the pure alanyl package, owing to hydrogen bonding between serine hydroxyls and carbonyl oxygens. The energy profile for sodium as well as the water-channel interactions are favored by the presence of the OH groups and by the lability of the seryl side chains. The possible general significance of the results is suggested.

A theoretical study of the effect of structural variations on the biochemical reactivity of yeast tRNAPhe and yeast tRNAAsp

The ASIF index which combines both steric and electronic factors is applied to the comparative study of the reactivity of yeast tRNAAsp and yeast tRNAPhe using the coordinates deduced from their crystal structures. The results compared with the known experimental reactivities in solution are somewhat less perfect for tRNAAsp than for tRNAPhe. The reasons for this situation are probably related to the differences existing between the structures of tRNAAsp in the crystal and in solution.

Structure, Dynamics and Function of Hydrogen-Bonded Networks in Proteins and Related Systems

The hydrogen bond plays an important role in living systems. In a hydrated, folded globular protein hydrogen bonds will be present between the water molecules, between water and protein groups and within the protein. A primary task in molecular biophysics is the determination of the physical properties of these hydrogen bonds and their role in determining the structure, dynamics and functioning of globular proteins.

On the Configurations Accessible to Folded and to Denatured Proteins

The determination of the configurations accessible to native and denatured states of globular proteins is required for an understanding of protein folding and function. X-ray crystallography and NMR spectroscopy furnish detailed information on the average structures of folded proteins. The configurations accessible to most folded proteins can be described in terms of fluctuations of the atoms of ~ 1 A about their average positions. Data on the configurations accessible to denatured proteins are much harder to obtain. An idealised model for a denatured protein is that of the ‘random coil’ involving a completely unfolded chain randomly sampling conformations limited only by steric requirements. Alternatively, intramolecular protein-protein associations can occur, such that some structure remains in what is traditionally assumed to be a ‘fully denatured’ state.