Fatty acid binding to serum albumin: Molecular simulation approaches

Background: Binding affinity for human serum albumin (HSA) is one of the most important factors affecting the distribution and free blood concentration of many ligands. The effect of fatty acids (FAs) on HSA-ligand binding has long been studied. Since the elucidation of the 3-dimensional structure of HSA, molecular simulation approaches have been applied to studies of the structure-function relationship of HSA-FA binding. Scope of review: We review current insights into the effects of FA binding on HSA, focusing on the biophysical insights obtained using molecular simulation approaches such as docking, molecular dynamics (MD), and binding free energy calculations. Major conclusions: Possible conformational changes on binding of FA molecules to HSA have been observed through MD simulations. High- and low-affinity FA-binding sites on HSA have been identified based on binding free energy calculations. The relationship between the warfarin binding affinity of HSA and FA molecules has been clarified based on the results of simulations of multi-site FA binding that cannot be experimentally observed. General significance: Molecular simulation approaches have great potentials to provide detailed biophysical insights into HSA as well as the effects of the binding of FAs or other ligands to HSA. This article is part of a Special Issue entitled Serum Albumin

Molecular dynamics study of conformational changes in human serum albumin by binding of fatty acids

Human serum albumin (HSA) binds with fatty acids under normal physiologic conditions. To date, there is little published information on the tertiary structure of HSA-fatty acid complex in aqueous solution. In the present study, we used molecular dynamics (MD) simulations to elucidate possible structural changes of HSA brought about by the binding of fatty acids. Both unliganded HSA and HSA-fatty acid complex models for MD calculations were constructed based on the X‐ray crystal structures. Five myristates (MYRs) were bound in the HSA-fatty acid complex model. In the present MD study, the motion of domains I and III caused by the binding of MYR molecules increased the radius of gyration of HSA. Root‐mean‐square fluctuations from the MD simulations revealed that the atomic fluctuations of the specific amino acids at drug‐binding site I that can regulate the drug‐binding affinity were increased by the binding of MYR molecules. Primary internal motions, characterized by the first three principal components, were observed mainly at domains I and III in the principal component analysis for trajectory data. The directional motion projected on the first principal component of unliganded HSA was conserved in HSA-MYR complex as the third principal directional motion with higher frequency. However, the third principal directional motion in unliganded HSA turned into the first principal directional motion with lower frequency in the HSA-MYR complex. Thus, the present MD study provides insights into the possible conformational changes of HSA caused by the binding of fatty acids. Proteins 2006. © 2006 Wiley‐Liss, Inc

Molecular dynamics study on conformational differences between dGMP and 8-oxo-dGMP: Effects of metal ions

The modified nucleotide base 7,8-dihydro-8-oxo-guanine (8-oxo-G) is one of the major sources of spontaneous mutagenesis. Nucleotide-sanitizing enzymes, such as the MutT homolog-1 (MTH1) and nudix-type motif 5 (NUDT5), selectively remove 8-oxo-G from the cellular pool of nucleotides. Previous studies showed that, although the syn conformation generally predominates in purine nucleotides with a bulky substituent at the 8-position, 8-oxo-dGMP binds to both MTH1 and NUDT5 in the anti conformation. This study was initiated to investigate the possibility that 8-oxo-dGMP itself may adopt the anti conformation. Molecular dynamics simulations of mononucleotides (dGMP, 8-oxo-dGMP) in aqueous solution were performed. 8-oxo-dGMP adopted the anti conformation as well as the syn conformation, and the proportion of adopting the anti conformation increased in the presence of metal ions. When 8-oxo-dGMP was in the anti conformation, a metal ion was located between the oxygen atom of phosphate and the oxygen atom at the 8-position of 8-oxo-G. The types of stable anti conformations of 8-oxo-dGMP differed, depending on the ionic radii and charges of coexisting ions. These data suggested a role for metal ions, other than as cofactors for the hydrolysis of the di- and tri-phosphate forms of mononucleotides; that the metal ions help retain the anti conformation of the N-glycosidic torsion angle of 8-oxo-dGMP to promote the binding between the 8-oxo-G deoxynucleotide and the nucleotide-sanitizing enzymes

Sample Entropy in Electrocardiogram During Atrial Fibrillation

【Background】 Atrial fibrillation (AF) is an arrhythmia commonly encountered in clinical practice. There is a high risk of thromboembolism in patients with AF. Nonlinear analyses such as electroencephalogram (EEG), electrocardiogram (ECG), and respiratory movement have been used to quantify biological signals, and sample entropy (SampEn) has been employed as a statistical measure to evaluate complex systems. In this study, we examined the values of SampEn in ECG signals for patients with and without AF to measure the regularity and complexity. 【Methods】 ECG signals of lead II were recorded from 34 subjects without arrhythmia and 15 patients with chronic AF in a supine position. The ECG signals were converted into time-series data and SampEn was calculated. 【Results】 The SampEn values for the group without arrhythmia were 0.252 ± 0.114 [time lag (τ) = 1] and 0.533 ± 0.163 (τ = 5), and those for the chronic AF group were 0.392 ± 0.158 (τ = 1) and 0.759 ± 0.246 (τ = 5). The values of SampEn were significantly higher in the group with chronic AF than in the group without arrhythmia (P < 0.01 for τ = 1, P < 0.004 for τ = 5). The constructed three-dimensional vectors were plotted in time-delayed three-dimensional space. We used time lags of τ = 5 and τ = 1. The shape of the loops of the three-dimensional space was better for τ = 5. 【Conclusion】 The values of SampEn from ECG for chronic AF patients were higher than for subjects without arrhythmia, suggesting greater complexity for the time-series from chronic AF patients. SampEn is considered a new index for evaluating complex systems in ECG

Steric and Allosteric Effects of Fatty Acids on the Binding of Warfarin to Human Serum Albumin Revealed by Molecular Dynamics and Free Energy Calculations

Human serum albumin (HSA) binds with drugs and fatty acids (FAs). This study was initiated to elucidate the relationship between the warfarin binding affinity of HSA and the positions of bound FA molecules. Molecular dynamics simulations of 11 HSA-warfarin-myristate complexes were performed. HSA-warfarin binding free energy was then calculated for each of the complexes by the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method. The results indicated that the magnitude of the binding free energy was smaller in HSA-warfarin complexes that had 4 or more myristate molecules than in complexes with no myristate molecules. The unfavorable effect on the HSA-warfarin binding affinity was caused sterically by the binding of a myristate molecule to the FA binding site closest to the warfarin binding site. On the other hand, the magnitude of HSA-warfarin binding free energy was largest when 3 myristate molecules were bound to the high-affinity sites. The strongest HSA-warfarin binding was attributable to favorable entropic contribution related to larger atomic fluctuations of the amino acid residues at the warfarin binding site. In the binding of 2 myristate molecules to the sites with the highest and second-highest affinities, allosteric modulation that enhanced electrostatic interactions between warfarin and some of the amino acid residues around the warfarin binding site was observed. This study clarified the structural and energetic properties of steric/allosteric effects of FAs on the HSA-warfarin binding affinity and illustrated the approach to analyze protein-ligand interactions in situations such that multiple ligands bind to the other sites of the protein