Evaluation of binding and antagonism/downregulation of brilanestrant molecule in estrogen receptor-α via quantum mechanics/molecular mechanics,molecular dynamics and binding free energy calculations

Abstract

The resistance to the endocrine therapy of breast cancer leads to the emergence of new class of drugs that downregulates the estrogen receptor action known as selective estrogen receptor downregulators (SERDs). The first approved SERD is fluvestrant; after this, there are several downregulators evolved and are in clinical trials, in which the brilanestrant (BRI) molecule shows nM range of binding affinity and efficacy. In the present study, to understand the binding nature of BRI molecule in the active site of ERα, the molecular docking analysis has been performed. Further, the QM/MM calculations were performed for the BRI–ERα complex to analyze the charge density distribution of intermolecular interactions. The molecular dynamics (MD) simulation was employed to understand the stability and binding mechanism of BRI molecule through root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF) and binding free energy calculations. From the MD simulation trajectory analysis, the alterations of Helix12 conformation and the key residue (Lys529), which is responsible for the ERα downregulation, have been identified. Further, the interaction between the H3 and H12 regions was identified for the antagonism of BRI molecule. The current study led us to understand the binding mechanism, antagonism and downregulation of BRI molecule, and this knowledge is essential to design novel SERDs for the treatment of endocrine-resistant positive breast cancer.

Communicated by Ramaswamy H. Sarma     

HIV-1跨膜蛋白gp41与N-取代吡咯衍生物的结合模式研究

采用分子对接,分子动力学(MD)模拟和分子力学/泊松-波尔兹曼溶剂可有面积方法与分子力学/广义伯恩溶剂可及面积方法(MM-PBSA/MM-GBSA),预测两种N-取代吡咯衍生物与HIV-1 跨膜蛋白gp41疏水口袋的结合模式与作用机理．分子对接采用多种受体构象,并从结果中选取几种可能的结合模式进行MD 模拟,然后通过MM-PBSA计算结合能的方法识别最优的结合模式. MM-PBSA计算结果表明,范德华相互作用是结合的主要驱动力,而极性相互作用决定了配体在结合过程中的取向．进一步的结合能分解显示,配体的羧基与gp41残基Arg579的静电相互作用对结合有重要贡献．上述工作为进一步优化N-取代吡咯衍生物类的HIV-1融合抑制剂建立了良好的理论基础．     

Modeling the interaction of seven bisphosphonates with the hydroxyapatite(100) face

The interaction of seven pamidronate bisphosphonate (Pami-BPs) and its analogs with the hydroxyapatite (HAP) (100) surface was studied using density functional theory (DFT) and molecular dynamic (MD) methods. Partial Mulliken oxygen atomic charges in protonated structures were calculated at the level of B3LYP/6-31G*. The MD simulation was performed using the Discover module of Material Studio by compass force field. The results indicate the abilities of donating electrons of the oxygen atoms of the phosphate groups that are closely associated with the antiresorptive potency. The binding energies, including vdw and electrostatic, are used to discuss the mechanism of antiresorption. The results of calculations show that the strength of interaction of the HAP (100) face with the bisphosphonates is N(4)?>?N(6)?>?N(7)?>?N(5)?>?N(3)?>?N(2)?>?N(1) according to their experimental pIC(50) values.     

Molecular dynamics studies on mutants of Cu,Zn superoxide dismutase: The functional role of charged residues in the electrostatic loop VII

Molecular dynamics (MD) calculations have been performed on mutants of superoxide dismutase (SOD) on some residues present in the electrostatic loop. These calculations have provided the solution structures for the mutants Thr-137 → IIe and Arg; Lys-136 → Ala; Glu-132 → Gln; Glu-133 → Gln; Glu-132, Glu-133 → Gln-132, Gln-133 and → Gln-132, Lys-133. The structural and dynamic properties of these mutants have been correlated with the catalytic properties and available spectroscopic data. The water molecule present in the active site close to the copper ion in wild type (WT) SOD is missing in the MD average structure of the Thr-137 → IIe mutant, while this molecule is present in the MD average structures of all the other mutants and of WT SOD. This agrees with the experimental data. This is an important result that shows the validity of our calculations and their ability to reproduce even subtle structural features. Addition of one or more positive charges on the 132 and/or 133 positions does not sizably perturb the structure of the active site channel, while the introduction of a positively charged residue (Arg) on position 137 has a large effect on the structure of the electrostatic loop. Analysis of the MD average structures of these mutants has pointed out that the simple electrostatic effects of charged residues in the channel are not the only factor relevant for enzymatic behavior but that the structure of the electrostatic loop and the location of the charged residues also contribute to the catalytic properties of SOD. © 1994 John Wiley & Sons, Inc.     

Hydrogen bonding of flavoprotein: II. Effect of hydrogen bonding at hetero atoms of reduced flavin on its reactivity

The effect of hydrogen bonding at hetero atoms of reduced flavin on its reactivity was studied by ab initio molecular orbital calculations. Among the atoms in the isoalloxazine nucleus of lumiflavin, C(4a) was found to be the most reactive with neutral electrophiles such as molecular oxygen, whereas no reactivity of N(5) can be expected, because of its negative charge. The reactivity of C(4a) is markedly enhanced by hydrogen bonding at N(1) and N(3) in a hydrophobic environment, while it is decreased when hydrogen bonding occurs at all the hetero atoms, as in the case of an aqueous solution of flavin.     

Investigation of glucose binding sites on insulin

Possible insulin binding sites for D-glucose have been investigated theoretically by docking and molecular dynamics (MD) simulations. Two different docking programs for small molecules were used; Multiple Copy Simultaneous Search (MCSS) and Solvation Energy for Exhaustive Docking (SEED) programs. The configurations resulting from the MCSS search were evaluated with a scoring function developed to estimate the binding free energy. SEED calculations were performed using various values for the dielectric constant of the solute. It is found that scores emphasizing non-polar interactions gave a preferential binding site in agreement with that inferred from recent fluorescence and NMR NOESY experiments. The calculated binding affinity of -1.4 to -3.5 kcal/mol is within the measured range of -2.0 +/- 0.5 kcal/mol. The validity of the binding site is suggested by the dynamical stability of the bound glucose when examined with MD simulations with explicit solvent. Alternative binding sites were found in the simulations and their relative stabilities were estimated. The motions of the bound glucose during molecular dynamics simulations are correlated with the motions of the insulin side chains that are in contact with it and with larger scale insulin motions. These results raise the question of whether glucose binding to insulin could play a role in its activity. The results establish the complementarity of molecular dynamics simulations and normal mode analyses with the search for binding sites proposed with small molecule docking programs.     

Interpreting the structural mechanism of action for MT7 and human muscarinic acetylcholine receptor 1 complex by modeling protein–protein interaction

MT7 is a selective human muscarinic acetylcholine receptor 1 (hM1) allosteric binder with subnanomolar affinity. Understanding the binding mode of hM1–MT7 will give insights to discover small molecular ligand for hM1. MT7 is a peptide, and hM1 is a G-protein-coupled membrane receptor. Therefore, we have employed homology modeling, protein–protein docking, explicit membrane molecular dynamics (MD) simulations, and molecular mechanic/Poisson-Boltzmann surface area energy decomposition analysis approaches to reveal the hM1–MT7 binding mode. The binding mode is consistent with the experimental data. We have discovered that the binding mode consists of three interaction regions in five residue interaction clusters. By analyzing the cluster representative structures, the cluster residues form an interaction network, which shows a multiple-point-to-site binding mode. Hydrogen binding statistical analysis reveals that E170 (hM1) and R34 (MT7) are both locked in electrostatic cages with counter charges, respectively. This is confirmed by the dynamic distances calculation between these residues, and biological mutant experiments.     

Novel insights into the dynamics behavior of glucagon-like peptide-1 receptor with its small molecule agonists

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is a well-known target of therapeutics industries for the treatment of various metabolic diseases like type 2 diabetes and obesity. The structural–functional relationships of small molecule agonists and GLP-1R are yet to be understood. Therefore, an attempt was made on structurally known GLP-1R agonists (Compound 1, Compound 2, Compound A, Compound B, and (S)-8) to study their interaction with the extracellular domain of GLP-1R. In this study, we explored the dynamics, intrinsic stability, and binding mechanisms of these molecules through computational modeling, docking, molecular dynamics (MD) simulations and molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) binding free energy estimation. Molecular docking study depicted that hydrophobic interaction (pi–pi stacking) plays a crucial role in maintaining the stability of the complex, which was also supported by intermolecular analysis from MD simulation study. Principal component analysis suggested that the terminal ends along with the turns/loops connecting adjacent helix and strands exhibit a comparatively higher movement of main chain atoms in most of the complexes. MM/PBSA binding free energy study revealed that non-polar solvation (van der Waals and electrostatic) energy subsidizes significantly to the total binding energy, and the polar solvation energy opposes the binding agonists to GLP-1R. Overall, we provide structural features information about GLP-1R complexes that would be conducive for the discovery of new GLP-1R agonists in the future for the treatment of various metabolic diseases.

Communicated by Ramaswamy H. Sarma     

Searching the conformational complexity and binding properties of HDAC6 through docking and molecular dynamic simulations

Histone deacetylases (HDACs) are a family of proteins involved in the deacetylation of histones and other non-histones substrates. HDAC6 belongs to class II and shares similar biological functions with others of its class. Nevertheless, its three-dimensional structure that involves the catalytic site remains unknown for exploring the ligand recognition properties. Therefore, in this contribution, homology modeling, 100-ns-long Molecular Dynamics (MD) simulation and docking calculations were combined to explore the conformational complexity and binding properties of the catalytic domain 2 from HDAC6 (DD2-HDAC6), for which activity and affinity toward five different ligands have been reported. Clustering analysis allowed identifying the most populated conformers present during the MD simulation, which were used as starting models to perform docking calculations with five DD2-HDAC6 inhibitors: Cay10603 (CAY), Rocilinostat (RCT), Tubastatin A (TBA), Tubacin (TBC), and Nexturastat (NXT), and then were also submitted to 100-ns-long MD simulations. Docking calculations revealed that the five inhibitors bind at the DD2-HDAC6 binding site with the lowest binding free energy, the same binding mode is maintained along the 100-ns-long MD simulations. Overall, our results provide structural information about the molecular flexibility of apo and holo DD2-HDAC6 states as well as insight of the map of interactions between DD2-HDAC6 and five well-known DD2-HDAC6 inhibitors allowing structural details to guide the drug design. Finally, we highlight the importance of combining different theoretical approaches to provide suitable structural models for structure-based drug design.     

Reduced point charge models of proteins: assessment based on molecular dynamics simulations

A reduced point charge distribution is used to model Ubiquitin and two complexes, Vps27 UIM-1–Ubiquitin and Barnase–Barstar. It is designed from local extrema in charge density distributions obtained from the Poisson equation applied to smoothed molecular electrostatic potentials. A variant distribution is built by locating point charges on atoms. Various charge fitting conditions are selected, i.e. from either electrostatic Amber99 (Assisted Model Building with Energy Refinement) Coulomb potential or forces, considering reference grid points located within various distances from the protein atoms, with or without separate treatment of main and side chain charges. The program GROMACS (Groningen Machine for Chemical Simulations) is used to generate Amber99SB molecular dynamics (MD) trajectories of the solvated proteins modelled using the various reduced point charge models (RPCMs) so obtained. Point charges that are not located on atoms are considered as virtual sites. Some RPCMs lead to stable MD trajectories. They, however, involve a partial loss in the protein secondary structure and lead to a less-structured solute solvation shell. The model built by fitting charges on Coulomb forces calculated at grid points ranging between 1.4 and 2.0 times the van der Waals radius of the atoms, with a separate treatment of main chain and side chain charges, appears to best approximate all-atom MD trajectories.     

Molecular mechanics PBSA ligand binding energy and interaction of Efavirenz derivatives with HIV-1 reverse transcriptase

In order to evaluate the properties of several HIV-1 reverse transcripase(RT) inhibitors, Efavirenz (SUSTIVA) and a set of its derivatives (benzoxazinones) have been placed into the nonnucleoside analogue binding site of the enzyme by molecular docking. The resulting geometries were used for a molecular dynamics simulation and binding energy calculations. The enzyme-inhibitor binding energies were estimated from experimental inhibitory activities (IC90). The correlation of the predicted and experimental binding energies were satisfactory acceptable as indicated by r2 = 0.865. Based on MD simulations, the obtained results indicate that the tight association of the ligand to the HIV-1 RT binding pocket was based on hydrogen bonding between Efavirenz's N1 and the oxygen of the backbone of Lys 101, with an estimated average distance of 1.88 A. Moreover, electrostatic interaction was mainly contributed by two amino acid residues in the binding site; Lys 101 and His 235. MD simulations open the possibility to study the reaction of the flexible enzyme to those substances as well as the overall affinity.     

Molecular modeling studies of substrate binding by penicillin acylase

Molecular modeling has revealed intimate details of the mechanism of binding of natural substrate, penicillin G (PG), in the penicillin acylase active center and solved questions raised by analysis of available X-ray structures, mimicking Michaelis complex, which substantially differ in the binding pattern of the PG leaving group. Three MD trajectories were launched, starting from PDB complexes of the inactive mutant enzyme with PG (1FXV) and native penicillin acylase with sluggishly hydrolyzed substrate analog penicillin G sulfoxide (1GM9), or from the complex obtained by PG docking. All trajectories converged to a similar PG binding mode, which represented the near-to-attack conformation, consistent with chemical criteria of how reactive Michaelis complex should look. Simulated dynamic structure of the enzyme-substrate complex differed significantly from 1FXV, resembling rather 1GM9; however, additional contacts with residues bG385, bS386, and bN388 have been found, which were missing in X-ray structures. Combination of molecular docking and molecular dynamics also clarified the nature of extremely effective phenol binding in the hydrophobic pocket of penicillin acylase, which lacked proper explanation from crystallographic experiments. Alternative binding modes of phenol were probed, and corresponding trajectories converged to a single binding pattern characterized by a hydrogen bond between the phenol hydroxyl and the main chain oxygen of bS67, which was not evident from the crystal structure. Observation of the trajectory, in which phenol moved from its steady bound to pre-dissociation state, mapped the consequence of molecular events governing the conformational transitions in a coil region a143-a146 coupled to substrate binding and release of the reaction products. The current investigation provided information on dynamics of the conformational transitions accompanying substrate binding and significance of poorly structured and flexible regions in maintaining catalytic framework.     

Modeling the interaction between anti-cancer drug penicillamine and pristine and functionalized carbon nanotubes for medical applications: density functional theory investigation and a molecular dynamics simulation

Abstract

The present study focuses on the prediction and investigation of binding properties of penicillamine with pure (5,5) single-walled carbon nanotube (SWCNT) and functionalized SWCNT (f-SWCNT) through the B3LYP and M06-2X functionals using the 6-31G** basis set. The electronic and structural properties, adsorption energy and frontier molecular orbitals of various configurations are examined. Our theoretical results indicated that the interaction of the nanotubes with penicillamine molecule is weak so that the drug adsorption process is typically physisorption. Also, results of theoretical calculations show that the adsorption of the drug molecule on f-SWCNT is stronger with shorter intermolecular distances in comparison to pure SWCNT. The natural bond orbital (NBO) analysis of studied systems demonstrates that the charge is transferred from penicillamine molecule to the nanotubes. Furthermore, molecular dynamics (MD) simulation is employed to evaluate the dynamic and diffusion behavior of drug molecule on SWCNT and f-SWCNT. Energy results show that drug molecule spontaneously moves toward the carriers, and the van der Waals energy contributions in drug adsorption are more than electrostatic interaction. The obtained results from MD simulation confirm that the functionalization of SWCNT leads to increase in the solubility of the carrier in aqueous solution.

Communicated by Ramaswamy H. Sarma     

A computational study of binding between 3-(4-fluorophenyl)-N-((4-fluorophenyl)sulphonyl)acrylamide and tubulin

3-(4-Fluorophenyl)-N-((4-fluorophenyl)sulphonyl)acrylamide (FFSA) is a potential tubulin polymerisation inhibitor. In this article, a theoretical study of the binding between FFSA and tubulin in colchicine site was carried out by molecular docking, molecular dynamics (MD) simulation and binding free energy calculations. The docking calculations preliminarily indicate that there are three possible binding modes 1, 2 and 3; MD simulations and binding free energy calculations identify that binding mode 2 is the most favourable, with the lowest binding free energy of ? 29.54 kcal/mol. Moreover, our valuable results for the binding are as follows: the inhibitor FFSA is suitably located at the colchicine site of tubulin, where it not only interacts with residues Leu248β, Lys254β, Leu255β, Lys352β, Met259β and Val181a by hydrophilic interaction, but also interacts with Val181α and Thr179α by hydrogen bond interaction. These two factors are both essential for FFSA strongly binding to tubulin. These theoretical results help understanding the action mechanism and designing new compounds with higher affinity to tubulin.     

Revealing chemical reactions of coal pyrolysis with GPU-enabled ReaxFF molecular dynamics and cheminformatics analysis

The complex chemistry of coal pyrolysis is difficult to be captured by experimental techniques or simulated with the quantum mechanics computational methods. The emerging of both the large-scale coal models and the promising capability of reactive molecular dynamics (ReaxFF MD) motivated us to develop a new methodology by combining graphics processing unit (GPU)-enabled high performance computing with cheminformatics analysis in order to explore the coal pyrolysis mechanisms using ReaxFF MD. The methodology is rooted in two new software tools, GMD-Reax, the first GPU-enabled ReaxFF MD codes that make it practical to simulate large-scale models (～10,000 atoms) on desktop workstations, and visualisation and analysis of reactive molecular dynamics (VARMD), the first software dedicated to analysis of detailed chemical reactions from the trajectories of ReaxFF MD simulation. With this methodology, reasonable product profiles and gas generation sequences of pyrolysis for bituminous coal models ranging from ～1000 to ～10,000 atoms (including the system with 28,351 atoms, one of the largest systems used in ReaxFF MD) have been obtained. The complex and detailed chemical reactions directly revealed by VARMD can provide further information on radical behaviours and their connection with pyrolysates. The methodology presented here offers a new and promising approach to systematically understand the complex chemical reactions in thermolysis of very complicated molecular systems.