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De Joannis J.,Emory University | De Joannis J.,Accelrys | Coppock P.S.,Emory University | Coppock P.S.,Georgia Institute of Technology | And 5 more authors.
Journal of the American Chemical Society

Mixed MD/MC simulation at fixed difference in chemical potential (Δμ) between two lipid types provides a computational indicator of the relative affinities of the two lipids for different environments. Applying this technique to ternary DPPC/DOPC/cholesterol bilayers yields a DPPC/DOPC ratio that increases with increasing cholesterol content at fixed Δμ, consistent with the known enrichment of DPPC and cholesterol-rich in liquid-ordered phase domains in the fluid-fluid coexistence region of the ternary phase diagram. Comparison of the cholesterol-dependence of PC compositions at constant Δμ with experimentally measured coexistence tie line end point compositions affords a direct test of the faithfulness of the atomistic model to experimental phase behavior. DPPC/DOPC ratios show little or no dependence on cholesterol content at or below 16% cholesterol in the DOPC-rich region of the composition diagram, indicating cooperativity in the favorable interaction between DPPC and cholesterol. The relative affinity of DPPC and DOPC for high cholesterol bilayer environments in simulations is explicitly shown to depend on the degree of cholesterol alignment with the bilayer normal, suggesting that a source of the cooperativity is the composition dependence of cholesterol tilt angle distributions. © 2011 American Chemical Society. Source

Ian I.-F.,Doctorate in Science in Biotechnology IPN | Luis R.-T.J.,SEPI ESCOM IPN | Luis R.-T.J.,Interdisciplinary Group on Artificial Intelligence Applied to Protein Folding | Pablo C.-V.J.,Doctorate in Science in Biotechnology IPN | And 15 more authors.
American Journal of Agricultural and Biological Science

Studies that include both experimental data and computational simulations (in silico) have increased in number because the techniques are complementary. In silico methodologies are currently an essential component of drug design; moreover, identification and optimization of the best ligand based on the structures of biomolecules are common scientific challenges. Geometric structural properties of biomolecules explain their behavior and interactions and when this information is used by a combination of algorithms, a dynamic model based on atomic details can be produced. Docking studies enable researchers to determine the best position for a ligand to bind on a macromolecule, whereas Molecular Dynamics (MD) simulations describe the relevant interactions that maintain this binding. MD simulations have the advantage of illustrating the macromolecule movements in more detail. In the case of a protein, the side chain, backbone and domain movements can explain how ligands are trapped during different conformational states. Additionally, MD simulations can depict several binding sites of ligands that can be explored by docking studies, sampling many protein conformations. Following the previously mentioned strategy, it is possible to identify each binding site that might be able to accommodate different ligands through atomic motion. Another important advantage of MD is to explore the movement of side chains of key catalytic residues, which could provide information about the formation of transition states of a protein. All this information can be used to propose ligands and their most probable site of interaction, which are daily tasks of drug design. In this review, the most frequent criteria that are considered when determining pharmacological targets are gathered, particularly when docking and MD are combined. © 2013 Science Publication. Source

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