Yves-Henri Sanejouand

Building-Block Approach for Determining Low-Frequency Normal Modes of Macromolecules

Normal mode analysis of proteins of various sizes, ranging from 46 (crambin) up to 858 residues (dimeric citrate synthase) were performed, by using standard approaches, as well as a recently proposed method that rests on the hypothesis that low‐frequency normal modes of proteins can be described as pure rigid‐body motions of blocks of consecutive amino‐acid residues. Such a hypothesis is strongly supported by our results, because we show that the latter method, named RTB, yields very accurate approximations for the low‐frequency normal modes of all proteins considered. Moreover, the quality of the normal modes thus obtained depends very little on the way the polypeptidic chain is split into blocks. Noteworthy, with six amino‐acids per block, the normal modes are almost as accurate as with a single amino‐acid per block. In this case, for a protein of n residues and N atoms, the RTB method requires the diagonalization of an n × n matrix, whereas standard procedures require the diagonalization of a 3N × 3N matrix. Being a fast method, our approach can be useful for normal mode analyses of large systems, paving the way for further developments and applications in contexts for which the normal modes are needed frequently, as for example during molecular dynamics calculations. Proteins 2000;41:1–7.

Long-range energy transfer in proteins

Proteins are large and complex molecular machines. In order to perform their function, most of them need energy, e.g. either in the form of a photon, as in the case of the visual pigment rhodopsin, or through the breaking of a chemical bond, as in the presence of adenosine triphosphate (ATP). Such energy, in turn, has to be transmitted to specific locations, often several tens of A away from where it is initially released. Here we show, within the framework of a coarse-grained nonlinear network model, that energy in a protein can jump from site to site with high yields, covering in many instances remarkably large distances. Following single-site excitations, few specific sites are targeted, systematically within the stiffest regions. Such energy transfers mark the spontaneous formation of a localized mode of nonlinear origin at the destination site, which acts as an efficient energy-accumulating center. Interestingly, yields are found to be optimum for excitation energies in the range of biologically relevant ones.

Conserved water molecules in family 1 glycosidases: a DXMS and molecular dynamics study.

By taking advantage of the wealth of structural data available for family 1 glycoside hydrolases, a study of the conservation of internal water molecules found in this ubiquitous family of enzymes was undertaken. Strikingly, seven water molecules are observed in more than 90% of the known structures. To gain insight into their possible function, the water dynamics inside Thermus thermophilus β-glycosidase was probed using deuterium exchange mass spectroscopy, allowing the pinpointing of peptide L117-A125, which exchanges most of its amide hydrogens quickly in spite of the fact that it is for the most part buried in the crystal structure. To help interpret this result, a molecular dynamics simulation was performed whose analysis suggests that two water channels are involved in the process. The longest one (∼16 Å) extends between the protein surface and W120, whose side chain interacts with E164 (the acid-base residue involved in the catalytic mechanism), whereas the other channel allows for the exchange with the bulk of the highly conserved water molecules belonging to the hydration shell of D121, a deeply buried residue. Our simulation also shows that another chain of highly conserved water molecules, going from the protein surface to the bottom of the active site cleft close to the nucleophile residue involved in the catalytic mechanism, is able to exchange with the bulk on the nanosecond time scale. It is tempting to speculate that at least one of these three water channels could be involved in the function of family 1 glycoside hydrolases.

Energy transfer in nonlinear network models of proteins

We investigate how nonlinearity and topological disorder affect the energy relaxation of local kicks in coarse-grained network models of proteins. We find that nonlinearity promotes long-range, coherent transfer of substantial energy to specific functional sites, while depressing transfer to generic locations. In some cases, transfer is mediated by the self-localization of discrete breathers at distant locations from the kick, acting as efficient energy-accumulating centers.

About some possible empirical evidences in favor of a cosmological time variation of the speed of light

Some empirical evidences in favor of the hypothesis that the speed of light decreases by a few centimeters per second each year are examined. Lunar laser ranging data are found to be consistent with this hypothesis, which also provides a straightforward explanation for the so-called Pioneer anomaly, that is, a time-dependent blue-shift observed when analyzing radio tracking data from distant spacecrafts, as well as an alternative explanation for both the apparent time-dilation of remote events and the apparent acceleration of the Universe. The main argument against this hypothesis, namely, the constancy of fine-structure and Rydberg constants, is discussed. Both of them being combinations of several physical constants, their constancy imply that, if the speed of light is indeed time-dependent, then at least two other “fundamental constants” have to vary as well. This defines strong constraints, which will have to be fulfilled by future varying-speed-of-light theories.

A singular mutation in the hemagglutinin of the 1918 pandemic virus

The influenza pandemic of 1918-1919 killed at least 50 million people. The reasons why this pandemic was so deadly remain largely unknown [9]. However, It has been shown that the 1918 viral hemagglutinin allows to reproduce the hallmarks of the illness observed during the original pandemic [11]. Thanks to the wealth of hemagglutinin sequences accumulated over the last decades, amino-acid substitutions that are found in the 1918-1919 sequences but rare otherwise can be identified with high confidence. Noteworthy, Gly 188, which is located within a key motif of the receptor binding site, has never been observed again in sequences of human viruses of subtype H1. Monitoring this singular mutation in viral sequences may help prevent another dramatic pandemic.