Identification of High Affinity Fatty Acid Binding Sites on Human Serum Albumin by MM-PBSA Method

Fujiwara, Sayaka; Amisaki, Takashi

doi:10.1529/biophysj.107.111377

Cited by 78 publications

(68 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been also reported that the binding affinity of an FA molecule at the site is much lower than that at the other FA binding sites. 9,17,29) Competitive binding of warfarin and myristate at drug binding site I was therefore not considered in this study.…”

Section: Results and Discussion Warfarin As The Target Drug In This Smentioning

confidence: 99%

“…17,29) FA binding sites 5, 4, and 2 are high-affinity sites, and 1 and 3 are low-affinity sites (Fig. 1).…”

Section: Methodsmentioning

confidence: 94%

“…12) In this study, 1 myristate molecule that bound to subdomain IIB was removed because the binding of FAs to this site was much weaker than that to the other sites. 9,17,29) Therefore, 1 warfarin and 5 myristate molecules were included in the subsequent MD simulations (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

“…In our previous study, 29) the binding free energy of a single palmitate or myristate molecule at each FA binding site was calculated using molecular dynamics (MD) simulations and the subsequent binding free energy calculations by the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) 30) method. The results of the calculations were consistent with the experimentally determined FA binding affinities.…”

mentioning

confidence: 99%

“…The results of the calculations were consistent with the experimentally determined FA binding affinities. 29) Using a similar approach, we calculated the binding free energies of a drug (warfarin) to HSA with FA molecules bound to various positions on HSA. Unlike conventional MM-PBSA applications which analyze simple protein-ligand binding systems, this study deals with the systems such that multiple ligands bind to the other sites of the protein.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

Fujiwara

Amisaki

2011

Chem. Pharm. Bull.

Self Cite

View full text Add to dashboard Cite

Human serum albumin (HSA) is the most abundant protein in blood plasma. It serves as a transport protein for several endogenous compounds such as nonesterified fatty acids (FAs), and is also capable of binding many commonly used drugs. Drug binding to HSA can result in a prolonged in vivo half-life. Thus, the binding of drugs to HSA is one of the most important factors determining their pharmacokinetics. 1)HSA consists of 585 amino acids and has a molecular mass of 66500 Da. The structure of HSA consists of 3 homologous domains (domains I-III), each of which is divided into 2 subdomains, A and B, having 6 and 4 a-helices, respectively (Fig. 1).2-4) Multiple ligand-binding sites have been reported for these subdomains. Two primary drug-binding sites, I (the warfarin binding site, located in subdomain IIA) and II (the indole-benzodiazepine site, located in subdomain IIIA), have received particular attention because of their high drug-binding affinity. 5,6) Seven FA binding sites have been also reported as common sites for medium-and long-chain FAs, 7) as well as for monosaturated and polyunsaturated FAs.8) Detailed studies on these sites have been performed by using X-ray crystallography, 7-12) site-directed mutagenesis, [13][14][15] and 13 C-NMR spectroscopy. 16,17) Under normal physiological conditions, HSA binds with approximately 0.1-2 mol FA per mol protein.18) The FA/HSA molar ratio can increase up to six during fasting or maximum exercise, 19,20) or in patients with diabetes. 21) In the high-ratio state, FA may affect the interactions between HSA and drugs because some FA binding sites overlap with drug binding sites I and II.12) Numerous studies have shown that drug binding to HSA can be modulated competitively or even cooperatively, by simultaneous binding of FAs. 1,12,[22][23][24][25][26][27] In the case of HSA-warfarin binding, it was reported that the addition of 2-4 mol of long-chain FAs per mol of HSA markedly increased the binding affinity of warfarin to HSA, whereas further addition of FAs decreased the affinity. 24)The effects of FAs on HSA-drug binding have been analyzed from the standpoint of the molecular structure. The binding of FA molecules to HSA can cause a relative rearrangement at the I-II and II-III domain interfaces 9,28) and conformational changes of the side chains of drug binding site I. 12) However, these studies are based on the HSA structures with all FA-accommodating sites being occupied by FA molecules. To date, there are no published works concerning the individual effect of FA binding to each site on 860 Vol. 59, No. 7 Regular Article Steric and Allosteric Effects of Fatty Acids on the Binding of Warfarin to Human Serum Albumin Revealed by Molecular Dynamics and Free Energy CalculationsShin-ichi FUJIWARA* and Takashi

show abstract

Section: Results and Discussion Warfarin As The Target Drug In This Smentioning

confidence: 99%

“…17,29) FA binding sites 5, 4, and 2 are high-affinity sites, and 1 and 3 are low-affinity sites (Fig. 1).…”

Section: Methodsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

Fujiwara

Amisaki

2011

Chem. Pharm. Bull.

Self Cite

View full text Add to dashboard Cite

show abstract

Interaction of Anesthetics with Globular Proteins

Nishimoto

Yamanaka

Matsuki

2016

Encyclopedia of Biocolloid and Biointerface Science 2V Set

View full text Add to dashboard Cite

Ligand entry into the calyx of β‐lactoglobulin

Bello

García‐Hernández

2014

Biopolymers

View full text Add to dashboard Cite

Although the thermodynamic principles that control the binding of drug molecules to their protein targets are well understood, the detailed process of how a ligand reaches a protein binding site has been an intriguing question over decades. The short time interval between the encounter between a ligand and its receptor to the formation of the stable complex has prevented experimental observations. Bovine β-lactoglobulin (βlg) is a lipocalin member that carries fatty acids (FAs) and other lipids in the cellular environment. Βlg accommodates a FA molecule in its highly hydrophobic cavity and exhibits the capability of recognizing a wide variety of hydrophobic ligands. To elucidate the ligand entry process on βlg, we report molecular dynamics simulations of the encounter between palmitate (PA) or laurate (LA) and βlg. Our results show that residues localized in loops at the cavity entrance play an important role in the ligand penetration process. Analysis of the short-term interaction energies show that the forces operating on the systems lead to average conformations very close to the crystallographic holo-forms. Whereas the binding free energy analysis using the molecular mechanics Generalized Born surface area method shows that these conformations were thermodynamically favorable.

show abstract

Identification of High Affinity Fatty Acid Binding Sites on Human Serum Albumin by MM-PBSA Method

Cited by 78 publications

References 48 publications

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

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

Interaction of Anesthetics with Globular Proteins

Ligand entry into the calyx of β‐lactoglobulin

Contact Info

Product

Resources

About