Biomedical subjects

Michel F Sanner

Publications and source records attributed to Michel F Sanner.

4 recordsLinked to original sources

PubMed2005

A component-based software environment for visualizing large macromolecular assemblies.

The interactive visualization of large biological assemblies poses a number of challenging problems, including the development of multiresolution representations and new interaction methods for navigating and analyzing these complex systems. An additional challenge is the development of flexible software environments that will facilitate the integration and interoperation of computational models and techniques from a wide variety of scientific disciplines. In this paper, we present a component-based software development strategy centered on the high-level, object-oriented, interpretive programming language: Python. We present several software components, discuss their integration, and describe some of their features that are relevant to the visualization of large molecular assemblies. Several examples are given to illustrate the interoperation of these software components and the integration of structural data from a variety of experimental sources. These examples illustrate how combining visual programming with component-based software development facilitates the rapid prototyping of novel visualization tools.

Capsid↗

PubMed2002

Model of the alphaLbeta2 integrin I-domain/ICAM-1 DI interface suggests that subtle changes in loop orientation determine ligand specificity.

The interaction of the alphaLbeta2 integrin with its cellular ligand the intercellular adhesion molecule-1 (ICAM-1) is critical for the tight binding interaction between most leukocytes and the vascular endothelium before transendothelial migration to the sites of inflammation. In this article we have modeled the alphaL subunit I-domain in its active form, which was computationally docked with the D1 domain of the ICAM-1 to probe potential protein-protein interactions. The experimentally observed key interaction between the carboxylate of Glu 34 in the ICAM-1 D1 domain and the metal ion-dependent adhesion site (MIDAS) in the open alphaL I-domain was consistently reproduced by our calculations. The calculations reveal the nature of the alphaLbeta2/ICAM-1 interaction and suggest an explanation for the increased ligand-binding affinity in the "open" versus the "closed" conformation of the alphaL I-domain. A mechanism for substrate selectivity among alphaL, alphaM, and alpha2 I-domains is suggested whereby the orientation of the loops within the I-domain is critical in mediating the interaction of the Glu 34 carboxylate of ICAM-1 D1 with the MIDAS.

Amino Acid Sequence↗

PubMed2002

Evolutionary analysis of HIV-1 protease inhibitors: Methods for design of inhibitors that evade resistance.

Drug-resistant strains are rapidly selected during AIDS therapy because of the high rate of mutation in HIV. In this report, we present an evolutionary simulation method for analysis of viral mutation and its use for optimization of HIV-1 protease drugs to improve their robustness in the face of resistance mutation. We first present an analysis of the range of resistant mutants that produce viable viruses by using a volume-based viral fitness model. Then, we analyze how this range of mutant proteases allows development of resistance to an optimal inhibitor previously designed by computational coevolution techniques. Finally, we evaluate the resistance patterns of commercially available drugs, and we discuss how resistance might be overcome by optimizing the size of specific side-chains of these inhibitors.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Automated docking to multiple target structures: incorporation of protein mobility and structural water heterogeneity in AutoDock.

Protein motion and heterogeneity of structural waters are approximated in ligand-docking simulations, using an ensemble of protein structures. Four methods of combining multiple target structures within a single grid-based lookup table of interaction energies are tested. The method is evaluated using complexes of 21 peptidomimetic inhibitors with human immunodeficiency virus type 1 (HIV-1) protease. Several of these structures show motion of an arginine residue, which is essential for binding of large inhibitors. A structural water is also present in 20 of the structures, but it must be absent in the remaining one for proper binding. Mean and minimum methods perform poorly, but two weighted average methods permit consistent and accurate ligand docking, using a single grid representation of the target protein structures.

Computer Simulation↗