Ab initio quantum mechanical study of the binding energies of human estrogen receptor α with its ligands: An application of fragment molecular orbital method

Abstract

We have theoretically examined the relative binding affinities (RBA) of typical ligands, 17beta-estradiol (EST), 17alpha-estradiol (ESTA), genistein (GEN), raloxifene (RAL), 4-hydroxytamoxifen (OHT), tamoxifen (TAM), clomifene (CLO), 4-hydroxyclomifene (OHC), diethylstilbestrol (DES), bisphenol A (BISA), and bisphenol F (BISF), to the alpha-subtype of the human estrogen receptor ligand-binding domain (hERalpha LBD), by calculating their binding energies. The ab initio fragment molecular orbital (FMO) method, which we have recently proposed for the calculations of macromolecules such as proteins, was applied at the HF/STO-3G level. The receptor protein was primarily modeled by 50 amino acid residues surrounding the ligand. The number of atoms in these model complexes is about 850, including hydrogen atoms. For the complexes with EST, RAL, OHT, and DES, the binding energies were calculated again with the entire ERalphaLBD consisting of 241 residues or about 4000 atoms. No significant difference was found in the calculated binding energies between the model and the real protein complexes. This indicates that the binding between the protein and its ligands is well characterized by the model protein with the 50 residues. The calculated binding energies relative to EST were very well correlated with the experimental RBA (the correlation coefficient r=0.837) for the ligands studied in this work. We also found that the charge transfer between ER and ligands is significant on ER-ligand binding. To our knowledge, this is the first achievement of ab initio quantum mechanical calculations of large molecules such as the entire ERalphaLBD protein.

Fragment molecular orbital calculations reveal that the E200K mutation markedly alters local structural stability in the human prion protein

“…Although the FMO calculations at the MP2 level can provide quantitative information on the molecular interactions between the residues in a protein, [12][13][14][15] such an analysis based on individual interactions involves enormous computational complexity; for example, PrP129-224, which contains ∼100 residues, could have more than 5,000 molecular interaction energies for residue pairs. Conversion of the intramolecular interactions between residues into those for secondary structure elements or pairs dramatically reduces the computational complexity and eases the interpretation of the calculation results.…”

“…10,11 This method has been used to quantify the inter-and intramolecular interactions in various proteins and nucleic acids-interactions that contribute to the binding affinities and structural stabilities of these molecules. [12][13][14][15] Very recently, this method has been successfully used to reveal the intermolecular interactions between PrP and an anti-prion drug. 15 In this study, we performed the FMO calculations on the globular domain of wild-type human PrP and the E200K variant in order to elucidate the differences in their intramolecular interactions and thus their local structural stabilities.…”

Pair interaction energy decomposition analysis

“…Perhaps the fragmentation mechanism with the BDA division in the FMO method aggravates the problem of introducing such free state, whose definition for covalently bound fragments is given later. (17) where DE CT,EDA is the charge transfer energy in EDA. The free state internal binding (IB0) gives a close estimate of the total amount of energy gained by producing the molecular system from monomers in their free state.…”

“…Filling the gap, we propose such analysis based upon the fragment molecular orbital (FMO) method, 15,16 which prescribes the division of molecules into fragments and leads to ab initio calculations of fragments, their dimers and, optionally, trimers. Quantum mechanical calculations of very large systems [17][18][19][20] become possible: Ikegami et al 21 applied the FMO method to the study of the photosynthetic reaction center of Rhodopseudomonas viridis consisting of more than 20,000 atoms.…”

Ab initio fragment molecular orbital studies of influenza virus hemagglutinin–sialosaccharide complexes toward chemical clarification about the virus host range determination

“…Ab initio FMO method has been applied in large biochemical systems for quantum chemical analysis to molecular interaction [40][41][42][43][44][45]. In this method, HA-sialoside complex is divided into fragments, and MO calculations are carried out on each fragment and fragment pairs.…”