%0 Journal Article
%T A Molecular Dynamics Approach to Ligand-Receptor Interaction in the Aspirin-Human Serum Albumin Complex
%A H. Ariel Alvarez
%A Andr¨¦s N. McCarthy
%A J. Ra¨²l Grigera
%J Journal of Biophysics
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/642745
%X In this work, we present a study of the interaction between human serum albumin (HSA) and acetylsalicylic acid (ASA, C9H8O4) by molecular dynamics simulations (MD). Starting from an experimentally resolved structure of the complex, we performed the extraction of the ligand by means of the application of an external force. After stabilization of the system, we quantified the force used to remove the ASA from its specific site of binding to HSA and calculated the mechanical nonequilibrium external work done during this process. We obtain a reasonable value for the upper boundary of the Gibbs free energy difference (an equilibrium thermodynamic potential) between the complexed and noncomplexed states. To achieve this goal, we used the finite sampling estimator of the average work, calculated from the Jarzynski Equality. To evaluate the effect of the solvent, we calculated the so-called ¡°viscous work,¡± that is, the work done to move the aspirin in the same trajectory through the solvent in absence of the protein, so as to assess the relevance of its contribution to the total work. The results are in good agreement with the available experimental data for the albumin affinity constant for aspirin, obtained through quenching fluorescence methods. 1. Introduction Human serum albumin (HSA) is the most abundant plasma protein in the human body and plays an important role in drug transport and metabolism. Generally regarded as a nonspecific transport protein, HSA has been assigned a number of enzymatic properties [1¨C3]. Additionally, the enzymatic activity of HSA on different substrates and drugs has also been studied and documented. Nevertheless, the structural mechanism of this activity is yet unknown. To assess the structural basis of binding mechanisms, we evaluated the interaction between HSA and acetylsalicylic acid (ASA, C9H8O4) by means of molecular dynamics simulations (MD). Starting from an experimentally resolved structure of the complex, we extracted the ligand by means of the application of an external force, under near quasistatic conditions, thus evaluating the work involved in breaking the interactions present in the protein-ligand complex, and hence obtaining an upper boundary for the free energy of binding of the complex. We quantified the force used to remove the ASA from its specific site of binding to HSA and calculated the mechanical nonequilibrium external work done during this process. The aim of the present study is to calculate an upper boundary for the Gibbs free energy difference associated to that process, through the average work
%U http://www.hindawi.com/journals/jbp/2012/642745/