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Binding Free Energies (binding + free_energy)
Selected AbstractsAccurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitorsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 5 2008Kitiyaporn Wittayanarakul Abstract Binding free energies were calculated for the inhibitors lopinavir, ritonavir, saquinavir, indinavir, amprenavir, and nelfinavir bound to HIV-1 protease. An MMPB/SA-type analysis was applied to conformational samples from 3 ns explicit solvent molecular dynamics simulations of the enzyme-inhibitor complexes. Binding affinities and the sampled conformations of the inhibitor and enzyme were compared between different HIV-1 protease protonation states to find the most likely protonation state of the enzyme in the complex with each of the inhibitors. The resulting set of protonation states leads to good agreement between calculated and experimental binding affinities. Results from the MMPB/SA analysis are compared with an explicit/implicit hybrid scheme and with MMGB/SA methods. It is found that the inclusion of explicit water molecules may offer a slight advantage in reproducing absolute binding free energies while the use of the Generalized Born approximation significantly affects the accuracy of the calculated binding affinities. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] Exploring the primary electron acceptor (QA)-site of the bacterial reaction center from Rhodobacter sphaeroidesFEBS JOURNAL, Issue 4 2002Binding mode of vitamin K derivatives The functional replacement of the primary ubiquinone (QA) in the photosynthetic reaction center (RC) from Rhodobacter sphaeroides with synthetic vitamin K derivatives has provided a powerful tool to investigate the electron transfer mechanism. To investigate the binding mode of these quinones to the QA binding site we have determined the binding free energy and charge recombination rate from QA, to D+ (kAD) of 29 different 1,4-naphthoquinone derivatives with systematically altered structures. The most striking result was that none of the eight tested compounds carrying methyl groups in both positions 5 and 8 of the aromatic ring exhibited functional binding. To understand the binding properties of these quinones on a molecular level, the structures of the reaction center-naphthoquinone complexes were predicted with ligand docking calculations. All protein,ligand structures show hydrogen bonds between the carbonyl oxygens of the quinone and AlaM260 and HisM219 as found for the native ubiquinone-10 in the X-ray structure. The center-to-center distance between the naphthoquinones at QA and the native ubiquinone-10 at QB (the secondary electron acceptor) is essentially the same, compared to the native structure. A detailed analysis of the docking calculations reveals that 5,8-disubstitution prohibits binding due to steric clashes of the 5-methyl group with the backbone atoms of AlaM260 and AlaM249. The experimentally determined binding free energies were reproduced with an rmsd of ,,4 kJ·mol,1 in most cases providing a valuable tool for the design of new artificial electron acceptors and inhibitors. [source] Multiple ligand simultaneous docking: Orchestrated dancing of ligands in binding sites of proteinJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 10 2010Huameng Li Abstract Present docking methodologies simulate only one single ligand at a time during docking process. In reality, the molecular recognition process always involves multiple molecular species. Typical protein,ligand interactions are, for example, substrate and cofactor in catalytic cycle; metal ion coordination together with ligand(s); and ligand binding with water molecules. To simulate the real molecular binding processes, we propose a novel multiple ligand simultaneous docking (MLSD) strategy, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring. The work also compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems. The methodology proves robust through systematic testing against several diverse model systems: E. coli purine nucleoside phosphorylase (PNP) complex with two substrates, SHP2NSH2 complex with two peptides and Bcl-xL complex with ABT-737 fragments. In all cases, the final correct docking poses and relative binding free energies were obtained. In PNP case, the simulations also capture the binding intermediates and reveal the binding dynamics during the recognition processes, which are consistent with the proposed enzymatic mechanism. In the other two cases, conventional single-ligand docking fails due to energetic and dynamic coupling among ligands, whereas MLSD results in the correct binding modes. These three cases also represent potential applications in the areas of exploring enzymatic mechanism, interpreting noisy X-ray crystallographic maps, and aiding fragment-based drug design, respectively. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] Accurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitorsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 5 2008Kitiyaporn Wittayanarakul Abstract Binding free energies were calculated for the inhibitors lopinavir, ritonavir, saquinavir, indinavir, amprenavir, and nelfinavir bound to HIV-1 protease. An MMPB/SA-type analysis was applied to conformational samples from 3 ns explicit solvent molecular dynamics simulations of the enzyme-inhibitor complexes. Binding affinities and the sampled conformations of the inhibitor and enzyme were compared between different HIV-1 protease protonation states to find the most likely protonation state of the enzyme in the complex with each of the inhibitors. The resulting set of protonation states leads to good agreement between calculated and experimental binding affinities. Results from the MMPB/SA analysis are compared with an explicit/implicit hybrid scheme and with MMGB/SA methods. It is found that the inclusion of explicit water molecules may offer a slight advantage in reproducing absolute binding free energies while the use of the Generalized Born approximation significantly affects the accuracy of the calculated binding affinities. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] Prediction of pKa shifts in proteins using a combination of molecular mechanical and continuum solvent calculationsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 15 2004Bernd Kuhn Abstract The prediction of pKa shifts of ionizable groups in proteins is of great relevance for a number of important biological phenomena. We present an implementation of the MM-GBSA approach, which combines molecular mechanical (MM) and generalized Born (GB) continuum solvent energy terms, to the calculation of pKa values of a panel of nine proteins, including 69 individual comparisons with experiment. While applied so far mainly to the calculation of biomolecular binding free energies, we show that this method can also be used for the estimation of protein pKa shifts, with an accuracy around 1 pKa unit, even for strongly shifted residues. Our analysis reveals that the nonelectrostatic terms that are part of the MM-GBSA free energy expression are important contributors to improved prediction accuracy. This suggests that most of the previous approaches that focus only on electrostatic interactions could be improved by adding other nonpolar energy terms to their free energy expression. Interestingly, our method yields best accuracy at protein dielectric constants of ,int = 2,4, which is in contrast to previous approaches that peak at higher ,int , 8. An important component of our procedure is an intermediate minimization step of each protonation state involving different rotamers and tautomers as a way to explicitly model protein relaxation upon (de)protonation. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1865,1872, 2004 [source] Converging free energy estimates: MM-PB(GB)SA studies on the protein,protein complex Ras,RafJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 2 2004Holger Gohlke Abstract Estimating protein,protein interaction energies is a very challenging task for current simulation protocols. Here, absolute binding free energies are reported for the complex H-Ras/C-Raf1 using the MM-PB(GB)SA approach, testing the internal consistency and model dependence of the results. Averaging gas-phase energies (MM), solvation free energies as determined by Generalized Born models (GB/SA), and entropic contributions calculated by normal mode analysis for snapshots obtained from 10 ns explicit-solvent molecular dynamics in general results in an overestimation of the binding affinity when a solvent-accessible surface area-dependent model is used to estimate the nonpolar solvation contribution. Applying the sum of a cavity solvation free energy and explicitly modeled solute,solvent van der Waals interaction energies instead provides less negative estimates for the nonpolar solvation contribution. When the polar contribution to the solvation free energy is determined by solving the Poisson,Boltzmann equation (PB) instead, the calculated binding affinity strongly depends on the atomic radii set chosen. For three GB models investigated, different absolute deviations from PB energies were found for the unbound proteins and the complex. As an alternative to normal-mode calculations, quasiharmonic analyses have been performed to estimate entropic contributions due to changes of solute flexibility upon binding. However, such entropy estimates do not converge after 10 ns of simulation time, indicating that sampling issues may limit the applicability of this approach. Finally, binding free energies estimated from snapshots of the unbound proteins extracted from the complex trajectory result in an underestimate of binding affinity. This points to the need to exercise caution in applying the computationally cheaper "one-trajectory-alternative" to systems where there may be significant changes in flexibility and structure due to binding. The best estimate for the binding free energy of Ras,Raf obtained in this study of ,8.3 kcal mol,1 is in good agreement with the experimental result of ,9.6 kcal mol,1, however, further probing the transferability of the applied protocol that led to this result is necessary. © 2003 Wiley Periodicals, Inc. J Comput Chem 2: 238,250, 2003 [source] Can the calculation of ligand binding free energies be improved with continuum solvent electrostatics and an ideal-gas entropy correction?JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 12 2002Sonja M. Schwarzl Abstract The prediction of a ligand binding constant requires generating three-dimensional structures of the complex concerned and reliably scoring these structures. Here, the scoring problem is investigated by examining benzamidine-like inhibitors of trypsin, a system for which errors in the structures are small. Precise and consistent binding free energies for the inhibitors are determined experimentally for this test system. To examine possible improvement of scoring methods, we test the suitability of continuum electrostatics to account for solvation effects and use an ideal-gas entropy correction to account for the changes in the degrees of freedom of the ligand. The small observed root-mean-square deviation of 0.55 kcal/mol of the calculated relative to the experimental values indicates that the essentials of the binding process have been captured. Even though all six ligands make the same salt bridge and H-bonds to the protein, the electrostatic contribution varies among the ligands by as much as 2 kcal/mol. Moreover, although the ligands are rigid and similar in size, the entropic terms also significantly affect the relative binding affinities (by up to 2.7 kcal/mol). The present approach to solvation and entropy may allow the ranking of the ligands to be considerably improved at a cost that makes the method applicable to the optimization of lead compounds or to the screening of small collections of ligands. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 1143,1149, 2002 [source] Continuum molecular electrostatics, salt effects, and counterion binding,A review of the Poisson,Boltzmann theory and its modificationsBIOPOLYMERS, Issue 2 2008Grochowski Abstract This work is a review of the Poisson,Boltzmann (PB) continuum electrostatics theory and its modifications, with a focus on salt effects and counterion binding. The PB model is one of the mesoscopic theories that describes the electrostatic potential and equilibrium distribution of mobile ions around molecules in solution. It serves as a tool to characterize electrostatic properties of molecules, counterion association, electrostatic contributions to solvation, and molecular binding free energies. We focus on general formulations which can be applied to large molecules of arbitrary shape in all-atomic representation, including highly charged biomolecules such as nucleic acids. These molecules present a challenge for theoretical description, because the conventional PB model may become insufficient in those cases. We discuss the conventional PB equation, the corresponding functionals of the electrostatic free energy, including a connection to DFT, simple empirical extensions to this model accounting for finite size of ions, the modified PB theory including ionic correlations and fluctuations, the cell model, and supplementary methods allowing to incorporate site-bound ions in the PB calculations. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 93,113, 2008. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] Calculation of ligand-nucleic acid binding free energies with the generalized-born model in DOCKBIOPOLYMERS, Issue 2 2004Xinshan Kang Abstract The calculation of ligand-nucleic acid binding free energies is investigated by including solvation effects computed with the generalized-Born model. Modifications of the solvation module in DOCK, including introduction of all-atom parameters and revision of coefficients in front of different terms, are shown to improve calculations involving nucleic acids. This computing scheme is capable of calculating binding energies, with reasonable accuracy, for a wide variety of DNA-ligand complexes, RNA-ligand complexes, and even for the formation of double-stranded DNA. This implementation of GB/SA is also shown to be capable of discriminating strong ligands from poor ligands for a series of RNA aptamers without sacrificing the high efficiency of the previous implementation. These results validate this approach to screening large databases against nucleic acid targets. © 2003 Wiley Periodicals, Inc. Biopolymers 73:192,204, 2004 [source] Thiobarbiturates as Sirtuin Inhibitors: Virtual Screening, Free-Energy Calculations, and Biological TestingCHEMMEDCHEM, Issue 12 2008Urszula Uciechowska Abstract NAD+ -dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysine residues in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of these enzymes and may be future drugs for the treatment of cancer or neurodegenerative diseases. Herein we present the results from a protein-based virtual screen of a commercial database with subsequent biological testing of the most promising compounds. The combination of docking and in,vitro experimental testing resulted in the identification of novel sirtuin inhibitors with thiobarbiturate structure. To rationalize the experimental results, free-energy calculations were carried out by molecular mechanics Poisson,Boltzmann/surface area (MM-PBSA) calculations. A significant correlation between calculated binding free energies and measured Sirt2 inhibitory activities was observed. The analyses suggested a molecular basis for the interaction of the identified thiobarbiturate derivatives with human Sirt2. Based on the docking and MM-PBSA calculations we synthesized and tested five further thiobarbiturates. The MM-PBSA method correctly predicted the activity of the novel thiobarbiturates. The identified compounds will be used to further explore the therapeutic potential of sirtuin inhibitors. [source] Structure-Based Calculation of Binding Affinities of ,2A -Adrenoceptor AgonistsCHEMMEDCHEM, Issue 6 2007Balázs Balogh An atomic resolution structure of ,2a -adrenoceptor was constructed and 15 known agonists were docked into the optimized model and experimental binding free energies were estimated. The figure shows the binding of the agonist clonidine (sticks) to the core binding pocket of the adrenoceptor (blue cartoon, key residues are marked with sticks). [source] Exploring the primary electron acceptor (QA)-site of the bacterial reaction center from Rhodobacter sphaeroidesFEBS JOURNAL, Issue 4 2002Binding mode of vitamin K derivatives The functional replacement of the primary ubiquinone (QA) in the photosynthetic reaction center (RC) from Rhodobacter sphaeroides with synthetic vitamin K derivatives has provided a powerful tool to investigate the electron transfer mechanism. To investigate the binding mode of these quinones to the QA binding site we have determined the binding free energy and charge recombination rate from QA, to D+ (kAD) of 29 different 1,4-naphthoquinone derivatives with systematically altered structures. The most striking result was that none of the eight tested compounds carrying methyl groups in both positions 5 and 8 of the aromatic ring exhibited functional binding. To understand the binding properties of these quinones on a molecular level, the structures of the reaction center-naphthoquinone complexes were predicted with ligand docking calculations. All protein,ligand structures show hydrogen bonds between the carbonyl oxygens of the quinone and AlaM260 and HisM219 as found for the native ubiquinone-10 in the X-ray structure. The center-to-center distance between the naphthoquinones at QA and the native ubiquinone-10 at QB (the secondary electron acceptor) is essentially the same, compared to the native structure. A detailed analysis of the docking calculations reveals that 5,8-disubstitution prohibits binding due to steric clashes of the 5-methyl group with the backbone atoms of AlaM260 and AlaM249. The experimentally determined binding free energies were reproduced with an rmsd of ,,4 kJ·mol,1 in most cases providing a valuable tool for the design of new artificial electron acceptors and inhibitors. [source] Differential mechanisms for the inhibition of human cytochrome P450 1A2 by apigenin and genisteinJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 4 2010Hideaki Shimada Abstract The inhibitory effects of flavonoids on the human cytochrome P450 1A2 (CYP1A2) were examined. Among flavonoids tested, galangin, kaempferol, chrysin, and apigenin were potent inhibitors. Although apigenin belonging to flavones and genistein belonging to isoflavones are similar in the chemical structures, the inhibitory potencies for CYP1A2 were distinguished markedly between these two flavonoids. In computer-docking simulation, apigenin interacted with the same mode of cocrystallized ,-naphthoflavone in the active site of CYP1A2, and then the B ring of apigenin was placed close to the heme iron of the enzyme with a single orientation. In contrast, the docked genistein conformation showed two different binding modes, and the A ring of genistein was oriented to the heme iron of CYP1A2. Furthermore, the binding free energy of apigenin was lower than that of genistein. These results demonstrate a possible mechanism that causes the differential inhibitory potencies of apigenin and genistein for CYP1A2. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:230,234, 2010; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.20328 [source] Converging free energy estimates: MM-PB(GB)SA studies on the protein,protein complex Ras,RafJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 2 2004Holger Gohlke Abstract Estimating protein,protein interaction energies is a very challenging task for current simulation protocols. Here, absolute binding free energies are reported for the complex H-Ras/C-Raf1 using the MM-PB(GB)SA approach, testing the internal consistency and model dependence of the results. Averaging gas-phase energies (MM), solvation free energies as determined by Generalized Born models (GB/SA), and entropic contributions calculated by normal mode analysis for snapshots obtained from 10 ns explicit-solvent molecular dynamics in general results in an overestimation of the binding affinity when a solvent-accessible surface area-dependent model is used to estimate the nonpolar solvation contribution. Applying the sum of a cavity solvation free energy and explicitly modeled solute,solvent van der Waals interaction energies instead provides less negative estimates for the nonpolar solvation contribution. When the polar contribution to the solvation free energy is determined by solving the Poisson,Boltzmann equation (PB) instead, the calculated binding affinity strongly depends on the atomic radii set chosen. For three GB models investigated, different absolute deviations from PB energies were found for the unbound proteins and the complex. As an alternative to normal-mode calculations, quasiharmonic analyses have been performed to estimate entropic contributions due to changes of solute flexibility upon binding. However, such entropy estimates do not converge after 10 ns of simulation time, indicating that sampling issues may limit the applicability of this approach. Finally, binding free energies estimated from snapshots of the unbound proteins extracted from the complex trajectory result in an underestimate of binding affinity. This points to the need to exercise caution in applying the computationally cheaper "one-trajectory-alternative" to systems where there may be significant changes in flexibility and structure due to binding. The best estimate for the binding free energy of Ras,Raf obtained in this study of ,8.3 kcal mol,1 is in good agreement with the experimental result of ,9.6 kcal mol,1, however, further probing the transferability of the applied protocol that led to this result is necessary. © 2003 Wiley Periodicals, Inc. J Comput Chem 2: 238,250, 2003 [source] Computational alanine scanning of the 1:1 human growth hormone,receptor complexJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2002Shuanghong Huo Abstract The MM-PBSA (Molecular Mechanics,Poisson,Boltzmann surface area) method was applied to the human Growth Hormone (hGH) complexed with its receptor to assess both the validity and the limitations of the computational alanine scanning approach. A 400-ps dynamical trajectory of the fully solvated complex was simulated at 300 K in a 101 Å×81 Å×107 Å water box using periodic boundary conditions. Long-range electrostatic interactions were treated with the particle mesh Ewald (PME) summation method. Equally spaced snapshots along the trajectory were chosen to compute the binding free energy using a continuum solvation model to calculate the electrostatic desolvation free energy and a solvent-accessible surface area approach to treat the nonpolar solvation free energy. Computational alanine scanning was performed on the same set of snapshots by mutating the residues in the structural epitope of the hormone and the receptor to alanine and recomputing the ,Gbinding. To further investigate a particular structure, a 200-ps dynamical trajectory of an R43A hormone,receptor complex was simulated. By postprocessing a single trajectory of the wild-type complex, the average unsigned error of our calculated ,,Gbinding is ,1 kcal/mol for the alanine mutations of hydrophobic residues and polar/charged residues without buried salt bridges. When residues involved in buried salt bridges are mutated to alanine, it is demonstrated that a separate trajectory of the alanine mutant complex can lead to reasonable agreement with experimental results. Our approach can be extended to rapid screening of a variety of possible modifications to binding sites. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 15,27, 2002 [source] Solvent models for protein,ligand binding: Comparison of implicit solvent poisson and surface generalized born models with explicit solvent simulationsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 6 2001Linda Yu Zhang Abstract Solvent effects play a crucial role in mediating the interactions between proteins and their ligands. Implicit solvent models offer some advantages for modeling these interactions, but they have not been parameterized on such complex problems, and therefore, it is not clear how reliable they are. We have studied the binding of an octapeptide ligand to the murine MHC class I protein using both explicit solvent and implicit solvent models. The solvation free energy calculations are more than 103 faster using the Surface Generalized Born implicit solvent model compared to FEP simulations with explicit solvent. For some of the electrostatic calculations needed to estimate the binding free energy, there is near quantitative agreement between the explicit and implicit solvent model results; overall, the qualitative trends in the binding predicted by the explicit solvent FEP simulations are reproduced by the implicit solvent model. With an appropriate choice of reference system based on the binding of the discharged ligand, electrostatic interactions are found to enhance the binding affinity because the favorable Coulomb interaction energy between the ligand and protein more than compensates for the unfavorable free energy cost of partially desolvating the ligand upon binding. Some of the effects of protein flexibility and thermal motions on charging the peptide in the solvated complex are also considered. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 591,607, 2001 [source] Recognition of protonated aliphatic ,,,-diamines by coproporphyrin I tetraanion in waterJOURNAL OF PHYSICAL ORGANIC CHEMISTRY, Issue 2 2002Alejandro Flores-Villalobos Abstract Interactions of aliphatic ,,,-diamines [H2N(CH2)nNH2, 2,,,n,,,8] with coproporphyrin I tetraanion (CP) were studied by spectrophotometry, fluorimetry and 1H NMR spectroscopy in the pH range 7,10 and ionic strengths 0.01,0.1,M. Diprotonated diammonium cations induce dimerization of CP by forming 1:1 complexes with CP which undergo much stronger self-aggregation than free CP tetraanions. On increasing the number of methylene units n connecting the ammonium groups, the binding constants for the complex formation with monomeric CP (KL) increase but the dimerization constants of the resulting complexes decrease. A hydrophobic contribution to the binding free energy of ,1.6,±,0.2,kJ,mol,1 per methylene unit was obtained from the linear correlation of logKL values extrapolated to zero ionic strength vs the number of methylene units (n,=,2,6). A model for diammonium-induced porphyrin dimerization is proposed, which involves complexation of diammonium cations with CP monomer via a combination of electrostatic and hydrophobic interactions and subsequent formation of porphyrin face-to-face dimers in which diammonium cations serve as the stabilizing bridges via ion pairing to carboxylate groups of two CP monomeric units. Copyright © 2001 John Wiley & Sons, Ltd. [source] How Do Halogen Substituents Contribute to Protein-Binding Interactions?CHEMBIOCHEM, Issue 17 2008A Thermodynamic Study of Peptide Ligands with Diverse Aryl Halides Hallowed halogens: Ligands with fluorine, chlorine, bromine and iodine can often display enhanced binding affinity for their biomolecular receptors. The underlying thermodynamic driving forces, however, have rarely been studied. Using calorimetry and a series of aryl halide-containing peptides that bind a PDZ domain protein, we examined how binding free energy, enthalpy and entropy are perturbed when the position and identity of halogen substituents are varied. [source] A Simple Cytosine to G-Clamp Nucleobase Substitution Enables Chiral ,-PNAs to Invade Mixed-Sequence Double-Helical B-form DNACHEMBIOCHEM, Issue 15 2008Venugopal Chenna Dr. Watson,Crick recognition of double-helical B-form DNA by Chiral ,-PNAs: C,G-clamp (X) nucleobase substitution provides the necessary binding free energy for chiral ,-PNAs to invade mixed-sequence B-DNA. [source] | ||||||||||||||||||||||