Analysis of the structure and dynamics of human serum albumin

Cuya, Teobaldo

doi:10.1007/s00894-014-2450-y

Cited by 54 publications

(38 citation statements)

References 35 publications

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“…1) [8,9]. This structure is remarkable for its stability while also remaining flexible which allows the binding and transport of a wide range of molecules, both endogenous and exogenous [10]. HSA contains a free cysteine at position-34, which represents the main molecular site for thiolation, nitrosylation, and oxidation; all other cysteine residues are involved in internal disulfide bonds to stabilize the spatial conformation of the molecule [11][12][13].…”

Section: Albumin Structurementioning

confidence: 98%

Albumin in chronic liver disease: structure, functions and therapeutic implications

2015

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Human serum albumin is a critical plasma protein produced by the liver with a number of accepted clinical indications in chronic liver disease including management of circulatory and renal dysfunction in patients with ascites. Advanced cirrhosis is characterised by reduced albumin concentration as well as impaired albumin function as a result of specific structural changes and oxidative damage. Traditionally, the biologic and therapeutic role of albumin in liver disease was attributed to its oncotic effects but it is now understood that albumin has a wide range of other important physiologic functions such as immunomodulation, endothelial stabilisation, antioxidant effects and binding multiple drugs, toxins and other molecules. This review discusses the multifunctional properties of albumin and, in particular, the biologic and clinical implications of structural and functional changes of albumin that are associated with cirrhosis. Based on these insights, we explore the current and potential future therapeutic uses of albumin in liver disease.

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Section: Albumin Structurementioning

confidence: 98%

Albumin in chronic liver disease: structure, functions and therapeutic implications

2015

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“…Therefore, it is essential to understand how this major plasma carrier protein, capable of binding ligands at different binding sites, changes its conformation and stability upon binding a particular ligand at its specific binding site. Binding of food-derived ligands such as vitamin B12 [15], fatty acids [16], lupeol [17], and phloretin [18] have also been reported to stabilize the conformation of HSA. However, there is no comprehensive study using computational and experimental methods, which demonstrates the stabilization of HSA structure by the binding of biologically active food component.…”

Section: Introductionmentioning

confidence: 99%

Stabilization of Human Serum Albumin by the Binding of Phycocyanobilin, a Bioactive Chromophore of Blue-Green Alga Spirulina: Molecular Dynamics and Experimental Study

et al. 2016

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Phycocyanobilin (PCB) binds with high affinity (2.2 x 106 M-1 at 25°C) to human serum albumin (HSA) at sites located in IB and IIA subdomains. The aim of this study was to examine effects of PCB binding on protein conformation and stability. Using 300 ns molecular dynamics (MD) simulations, UV-VIS spectrophotometry, CD, FT-IR, spectrofluorimetry, thermal denaturation and susceptibility to trypsin digestion, we studied the effects of PCB binding on the stability and rigidity of HSA, as well as the conformational changes in PCB itself upon binding to the protein. MD simulation results demonstrated that HSA with PCB bound at any of the two sites showed greater rigidity and lower overall and individual domain flexibility compared to free HSA. Experimental data demonstrated an increase in the α-helical content of the protein and thermal and proteolytic stability upon ligand binding. PCB bound to HSA undergoes a conformational change to a more elongated conformation in the binding pockets of HSA. PCB binding to HSA stabilizes the structure of this flexible transport protein, making it more thermostable and resistant to proteolysis. The results from this work explain at molecular level, conformational changes and stabilization of HSA structure upon ligand binding. The resultant increased thermal and proteolytic stability of HSA may provide greater longevity to HSA in plasma.

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“…2. While our process did not design for this, the resulting candidate binding modes cover all the possible ligand positions found in crystallography for any human serum albumin-ligand complex, 56 which currently encompass 38 distinct structures deposited in the Protein Data Bank. These positions also include the possibility that ibuprofen in charged form binds in site PC up , which is experimentally confirmed as a binding location only for capric acid, thyroxine and iodipamide.…”

Section: Resultsmentioning

confidence: 99%

“…Molecular docking was used as an ancillary technique for a first screening of the protein surface, in search for binding cavities to be (potentially) occupied by ibuprofen. The positions determined included all of the binding pockets already known in crystallography for ligands bound to albumin, 56 plus a supplementary location in the lower region of the central protein cleft. The binding modes obtained were subsequently refined through MD simulations that allowed the protein to accommodate the ligand.…”

Section: Discussionmentioning

confidence: 99%

Multiple binding modes of ibuprofen in human serum albumin identified by absolute binding free energy calculations

Evoli

Mobley

Guzzi

et al. 2016

Phys. Chem. Chem. Phys.

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Human serum albumin possesses multiple binding sites and transports a wide range of ligands that include the anti-inflammatory drug ibuprofen. A complete map of the binding sites of ibuprofen in albumin is difficult to obtain in traditional experiments, because of the structural adaptability of this protein in accommodating small ligands. In this work, we provide a set of predictions covering the geometry, affinity of binding and protonation state for the pharmaceutically most active form (S– isomer) of ibuprofen to albumin, by using absolute binding free energy calculations in combination with classical molecular dynamics (MD) simulations and molecular docking. The most favorable binding modes correctly reproduce several experimentally identified binding locations, which include the two Sudlow's drug sites (DS2 and DS1) and the fatty acid binding sites 6 and 2 (FA6 and FA2). Previously unknown details of the binding conformations were revealed for some of them, and formerly undetected binding modes were found in other protein sites. The calculated binding affinities exhibit trends which seem to agree with the available experimental data, and drastically degrade when the ligand is modeled in a protonated (neutral) state, indicating that ibuprofen associates with albumin preferentially in its charged form. These findings provide a detailed description of the binding of ibuprofen, help to explain a wide range of results reported in the literature in the last decades, and demonstrate the possibility of using simulation methods to predict ligand binding to albumin.

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Analysis of the structure and dynamics of human serum albumin

Cited by 54 publications

References 35 publications

Albumin in chronic liver disease: structure, functions and therapeutic implications

Albumin in chronic liver disease: structure, functions and therapeutic implications

Stabilization of Human Serum Albumin by the Binding of Phycocyanobilin, a Bioactive Chromophore of Blue-Green Alga Spirulina: Molecular Dynamics and Experimental Study

Multiple binding modes of ibuprofen in human serum albumin identified by absolute binding free energy calculations

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