Biomedical subjects

Miguel X Fernandes

Publications and source records attributed to Miguel X Fernandes.

6 recordsLinked to original sources

PubMed2005

Lipid membrane-induced optimization for ligand-receptor docking: recent tools and insights for the "membrane catalysis" model.

Cells in living organisms are regulated by chemical and physical stimuli from their environment. Often, ligands interact with membrane receptors to trigger responses and Sargent and Schwyzer conceived a model to describe this process, "membrane catalysis". There is a notion that the physical organization of membranes can control the response of cells by speeding up reactions. We revisit the "membrane catalysis" model in the light of recent technical, methodological and theoretical advances and how they can be exploited to highlight the details of membrane mediated ligand-receptor interactions. We examine the possible effects that ligand concentration causes in the membrane catalysis and focus our attention in techniques used to determine the partition constant. The hypothetical diffusional advantage associated with membrane catalysis is discussed and the applicability of existing models is assessed. The role of in-depth location and orientation of ligands is explored emphasizing the contribution of new analysis methods and spectroscopic techniques. Results suggest that membranes can optimize the interaction between ligands and receptors through several different effects but the relative contribution of each must be carefully investigated. We certainly hope that the conjugation of the methodological and technical advances here reported will revive the interest in the membrane catalysis model.

Biomimetic Materials↗

PubMed2004

Interpretation of NMR relaxation properties of Pin1, a two-domain protein, based on Brownian dynamic simulations.

Many important proteins contain multiple domains connected by flexible linkers. Inter-domain motion is suggested to play a key role in many processes involving molecular recognition. Heteronuclear NMR relaxation is sensitive to motions in the relevant time scales and could provide valuable information on the dynamics of multi-domain proteins. However, the standard analysis based on the separation of global tumbling and fast local motions is no longer valid for multi-domain proteins undergoing internal motions involving complete domains and that take place on the same time scale than the overall motion. The complexity of the motions experienced even for the simplest two-domain proteins are difficult to capture with simple extensions of the classical Lipari-Szabo approach. Hydrodynamic effects are expected to dominate the motion of the individual globular domains, as well as that of the complete protein. Using Pin1 as a test case, we have simulated its motion at the microsecond time scale, at a reasonable computational expense, using Brownian Dynamic simulations on simplified models. The resulting trajectories provide insight on the interplay between global and inter-domain motion and can be analyzed using the recently published method of isotropic Reorientational Mode Dynamics which offer a way of calculating their contribution to heteronuclear relaxation rates. The analysis of trajectories computed with Pin1 models of different flexibility provides a general framework to understand the dynamics of multi-domain proteins and explains some of the observed features in the relaxation rate profile of free Pin1.

Anisotropy↗

PubMed2002

Brownian dynamics simulation of the unsaturated lipidic molecules oleic and docosahexaenoic acid confined in a cellular membrane.

A Brownian dynamics (BD) simulation of two unsaturated molecules, oleic and docosahexaenoic acid, in an environment that reproduces a cellular membrane, is presented. The results of the simulations, performed using mean-field potentials, were calibrated with experimental results obtained for oleic acid in a cellular membrane. The agreement between simulation and experimental results is excellent which validates subsequent simulation outcome for docosahexaenoic acid. This molecule is a major component of several cellular membranes thought to be involved in specific biological functions that require conformational changes of membrane components. The results for docosahexaenoic acid indicate that it is minimally influenced by temperature changes and that it presents great conformational variability.

Cell Membrane↗

PubMed2002

Brownian dynamics simulation of rigid particles of arbitrary shape in external fields.

We have developed a Brownian dynamics simulation algorithm to generate Brownian trajectories of an isolated, rigid particle of arbitrary shape in the presence of electric fields or any other external agents. Starting from the generalized diffusion tensor, which can be calculated with the existing HYDRO software, the new program BROWNRIG (including a case-specific subprogram for the external agent) carries out a simulation that is analyzed later to extract the observable dynamic properties. We provide a variety of examples of utilization of this method, which serve as tests of its performance, and also illustrate its applicability. Examples include free diffusion, transport in an electric field, and diffusion in a restricting environment.

Algorithms↗

PubMedDate not supplied

Comparing ligand interactions with multiple receptors via serial docking.

Standard uses of ligand-receptor docking typically focus on the association of candidate ligands with a single targeted receptor, but actual applications increasingly require comparisons across multiple receptors. This study demonstrates that comparative docking to multiple receptors can help to select homology models for virtual compound screening and to discover ligands that bind to one set of receptors but not to another, potentially similar, set. A serial docking algorithm is furthermore described that reduces the computational costs of such calculations by testing compounds against a series of receptor structures and discarding a compound as soon as it fails to satisfy specified bind/no bind criteria for each receptor. The algorithm also realizes substantial efficiencies by taking advantage of the fact that a ligand typically binds in similar conformations to similar receptors. Thus, once detailed docking has been used to fit a ligand into the first of a series of similar receptors, much less extensive calculations can be used for the remaining structures.

Algorithms↗

PubMedDate not supplied

Screening drug-like compounds by docking to homology models: a systematic study.

In the absence of an experimentally solved structure, a homology model of a protein target can be used instead for virtual screening of drug candidates by docking and scoring. This approach poses a number of questions regarding the choice of the template to use in constructing the model, the accuracy of the screening results, and the importance of allowing for protein flexibility. The present study addresses such questions with compound screening calculations for multiple homology models of five drug targets. A central result is that docking to homology models frequently yields enrichments of known ligands as good as that obtained by docking to a crystal structure of the actual target protein. Interestingly, however, standard measures of the similarity of the template used to build the homology model to the targeted protein show little correlation with the effectiveness of the screening calculations, and docking to the template itself often is as successful as docking to the corresponding homology model. Treating key side chains as mobile produces a modest improvement in the results. The reasons for these sometimes unexpected results, and their implications for future methodologic development, are discussed.

Computer Simulation↗