Development of a new tool for automatic building of mixed biological membranes models for molecular dynamics simulations

Abstract

The use of computer simulations as a tool for studying the most variable systems is a reality. The analysis of results from real and virtual experiments allows a better and general understanding of involved phenomena, leading to a more complete characterization of the studied systems. The application of simulations to the study of molecular systems gives us the possibility to observe the behavior, organization and interaction between the components in the atomic level and get important properties by using specific techniques, making these calculations an useful tool for physical-chemistry studies. Among countless techniques of computer simulations, Molecular Dynamics (MD) is one of the most widespread currently, because gives extremely satisfactory and reliable results. The incidence of allergic diseases like asthma, rhinitis, atopic dermatitis and food allergy are increasing drastically in the last decades, mainly among children. The traditional methods of prevention or treatment of such diseases are, in most cases, inefficient or impose on individuals a low life's quality. The drugs administered currently have inefficient antiallergic action or cause undesirable side effects, which brings us the need of developing new drugs for this type of treatment. Drugs developed from natural sources's compounds represent a large proportion of drugs available on market, which stimulates the search for new molecules on these sources. Among the natural compounds with proven antiallergic action, we can highlight the flavonoids. However, these substances have low solubility and are sensitive to photo-oxidation or photo degradation, which decreases its bioavailability. A substantial increase on the bioavailability of these drugs is gotten through the formation of inclusion complexes with a type of carrier molecules called cyclodextrins. Cyclodextrins are cyclic oligosaccharides composed of 6 (±-cyclodextrin), 7 (²-cyclodextrin) or 8 (³-cyclodextrin) glucopyranose units linked by ±-(1,4) glycosidic linkages. Due to the volume of their hydrophobic cavity, the ²-cyclodextrin is the most suitable for the drugs's transportation. Although they are used commercially in more than 30 drugs in the world, the way how inclusion complexes increases the bioavailability of drugs isn't still clear. There are some hypotheses based on indirect experimental observations, however, the process is far from being completely understood. One possibility to better understand the process of delivering the drug to the cell by the cyclodextrin is to perform Molecular Dynamics simulations of systems made of inclusion complexes of cyclodextrin/drug and biological membrane's models. The construction of this type of system is especially laborious when talking about the assembly the membrane. Thus, the development of tools that automate this task would be very useful. This project proposes the development of a software for automated construction of mixed membranes formed from phospholipid (POPC, Pope, DPPC, etc.) and cholesterol in different amounts, its subsequent balancing/thermalization on water solution by molecular dynamics's simulations and the availability of results (coordinates's files) in the group's website for free access of the scientific community.