共查询到20条相似文献,搜索用时 15 毫秒
1.
Molecular dynamics simulations in explicit solvent were applied to predict the hydration free energies for 23 small organic
molecules in blind SAMPL2 test. We found good agreement with experimental results, with an RMS error of 2.82 kcal/mol over
the whole set and 1.86 kcal/mol over all the molecules except several hydroxyl-rich compounds where we find evidence for a
systematic error in the force field. We tested two different solvent models, TIP3P and TIP4P-Ew, and obtained very similar
hydration free energies for these two models; the RMS difference was 0.64 kcal/mol. We found that preferred conformation of
the carboxylic acids in water differs from that in vacuum. Surprisingly, this conformational change is not adequately sampled
on simulation timescales, so we apply an umbrella sampling technique to include free energies associated with the conformational
change. Overall, the results of this test reveal that the force field parameters for some groups of molecules (such as hydroxyl-rich
compounds) still need to be improved, but for most compounds, accuracy was consistent with that seen in our previous tests. 相似文献
2.
3.
Heather A. Carlson Toan B. Nguyen Modesto Orozco William L. Jorgensen 《Journal of computational chemistry》1993,14(10):1240-1249
Absolute free energies of hydration have been computed for 13 diverse organic molecules using partial charges derived from ab initio 6-31G* wave functions. Both Mulliken charges and charges fit to the electrostatic potential surface (EPS) were considered in conjunction with OPLS Lennard–Jones parameters for the organic molecules and the TIP4P model of water. Monte Carlo simulations with statistical perturbation theory yielded relative free energies of hydration. These were converted to absolute quantities through perturbations to reference molecules for which absolute free energies of hydration had been obtained previously in TIP4P water. The average errors in the computed absolute free energies of hydration are 1.1 kcal/mol for the 6-31G* EPS charges and 4.0 kcal/mol for the Mulliken charges. For the EPS charges, the largest individual errors are under 2 kcal/mol except for acetamide, in which case the error is 3.7 kcal/mol. The hydrogen bonding between the organic solutes and water has also been characterized. © John Wiley & Sons, Inc. 相似文献
4.
Jensen KP 《The journal of physical chemistry. B》2008,112(6):1820-1827
Electrostatic interactions dominate the structure and free energy of biomolecules. To obtain accurate free energies involving charged groups from molecular simulations, OPLS-AA parameters have been reoptimized using Monte Carlo free energy perturbation. New parameters fit a self-consistent, experimental set of hydration free energies for acetate (Asp), propionate (Glu), 4-methylimidazolium (Hip), n-butylammonium (Lys), and n-propylguanidinium (Arg), all resembling charged residue side chains, including beta-carbons. It is shown that OPLS-AA free energies depend critically on the type of water model, TIP4P or TIP3P; i.e., each water model requires specific water-charged molecule interaction potentials. New models (models 1 and 3) are thus described for both water models. Uncertainties in relative free energies of charged residues are approximately 2 kcal/mol with the new parameters, due to variations in system setup (MAEs of ca. 1 kcal/mol) and noise from simulations (ca. 1 kcal/mol). The latter error of approximately 1 kcal/mol contrasts MAEs from standard OPLS-AA of up to 13 kcal/mol for the entire series of charged residues or up to 5 kcal/mol for the cationic series Lys, Arg, and Hip. The new parameters can be used directly in molecular simulations with no modification of neutral residues needed and are envisioned to be particular important in simulations where charged residues change environment. 相似文献
5.
The influence of electron correlation on reaction energies. The dimerization energies of BH3 and LiH
Reinhart Ahlrichs 《Theoretical chemistry accounts》1974,35(1):59-68
Results of rigorous computations employing extended Gaussian-type basis sets are reported for BH3, B2H6, LiH, and Li2H2 in their respective equilibrium geometries. The dimerization energy of BH3 is calculated as −20.7 kcal/mol within the Hartree-Fock approximation and as −36.6 kcal/mol if electron correlation is included.
The corresponding results for the dimerization of LiH are −47.3 kcal/mol and −48.3 kcal/mol. Partitioning of the correlation
energy contributions allows to attribute the effect of electron correlation to the increase of next neighbour bond interactions
on the dimerization of BH3 and LiH. The difficulties of accurate computations of reaction energies are discussed in detail. 相似文献
6.
7.
David L. Mobley Karisa L. Wymer Nathan M. Lim J. Peter Guthrie 《Journal of computer-aided molecular design》2014,28(3):135-150
Here, we give an overview of the small molecule hydration portion of the SAMPL4 challenge, which focused on predicting hydration free energies for a series of 47 small molecules. These gas-to-water transfer free energies have in the past proven a valuable test of a variety of computational methods and force fields. Here, in contrast to some previous SAMPL challenges, we find a relatively wide range of methods perform quite well on this test set, with RMS errors in the 1.2 kcal/mol range for several of the best performing methods. Top-performers included a quantum mechanical approach with continuum solvent models and functional group corrections, alchemical molecular dynamics simulations with a classical all-atom force field, and a single-conformation Poisson–Boltzmann approach. While 1.2 kcal/mol is still a significant error, experimental hydration free energies covered a range of nearly 20 kcal/mol, so methods typically showed substantial predictive power. Here, a substantial new focus was on evaluation of error estimates, as predicting when a computational prediction is reliable versus unreliable has considerable practical value. We found, however, that in many cases errors are substantially underestimated, and that typically little effort has been invested in estimating likely error. We believe this is an important area for further research. 相似文献
8.
Enrico O. Purisima Christopher R. Corbeil Traian Sulea 《Journal of computer-aided molecular design》2010,24(4):373-383
The SAMPL2 hydration free energy blind prediction challenge consisted of a data set of 41 molecules divided into three subsets:
explanatory, obscure and investigatory, where experimental hydration free energies were given for the explanatory, withheld
for the obscure, and not known for the investigatory molecules. We employed two solvation models for this challenge, a linear
interaction energy (LIE) model based on explicit-water molecular dynamics simulations, and the first-shell hydration (FiSH)
continuum model previously calibrated to mimic LIE data. On the 23 compounds from the obscure (blind) dataset, the prospectively
submitted LIE and FiSH models provided predictions highly correlated with experimental hydration free energy data, with mean-unsigned-errors
of 1.69 and 1.71 kcal/mol, respectively. We investigated several parameters that may affect the performance of these models,
namely, the solute flexibility for the LIE explicit-solvent model, the solute partial charging method, and the incorporation
of the difference in intramolecular energy between gas and solution phases for both models. We extended this analysis to the
various chemical classes that can be formed within the SAMPL2 dataset. Our results strengthen previous findings on the excellent
accuracy and transferability of the LIE explicit-solvent approach to predict transfer free energies across a wide spectrum
of functional classes. Further, the current results on the SAMPL2 test dataset provide additional support for the FiSH continuum
model as a fast yet accurate alternative to the LIE explicit-solvent model. Overall, both the LIE explicit-solvent model and
the FiSH continuum solvation model show considerable improvement on the SAMPL2 data set over our previous continuum electrostatics-dispersion
solvation model used in the SAMPL1 blind challenge. 相似文献
9.
Spiwok V Lipovová P Skálová T Vondrácková E Dohnálek J Hasek J Králová B 《Journal of computer-aided molecular design》2005,19(12):887-901
Summary Aromatic amino acid residues are often present in carbohydrate-binding sites of proteins. These binding sites are characterized
by a placement of a carbohydrate moiety in a stacking orientation to an aromatic ring. This arrangement is an example of CH/π
interactions. Ab initio interaction energies for 20 carbohydrate–aromatic complexes taken from 6 selected ultra-high resolution X-ray structures
of glycosidases and carbohydrate-binding proteins were calculated. All interaction energies of a pyranose moiety with a side
chain of an aromatic residue were calculated as attractive with interaction energy ranging from −2.8 to −12.3 kcal/mol as
calculated at the MP2/6-311+G(d) level. Strong attractive interactions were observed for a wide range of orientations of carbohydrate
and aromatic ring as present in selected X-ray structures. The most attractive interaction was associated with apparent combination
of CH/π interactions and classical H-bonds. The failure of Hartree–Fock method (interaction energies from +1.0 to −6.9 kcal/mol)
can be explained by a dispersion nature of a majority of the studied complexes. We also present a comparison of interaction
energies calculated at the MP2 level with those calculated using molecular mechanics force fields (OPLS, GROMOS, CSFF/CHARMM,
CHEAT/CHARMM, Glycam/AMBER, MM2 and MM3). For a majority of force fields there was a strong correlation with MP2 values. RMSD
between MP2 and force field values were 1.0 for CSFF/CHARMM, 1.2 for Glycam/AMBER, 1.2 for GROMOS, 1.3 for MM3, 1.4 for MM2,
1.5 for OPLS and to 2.3 for CHEAT/CHARMM (in kcal/mol). These results show that molecular mechanics approximates interaction
energies very well and support an application of molecular mechanics methods in the area of glycochemistry and glycobiology. 相似文献
10.
Gerhard König Frank C. Pickard IV Ye Mei Bernard R. Brooks 《Journal of computer-aided molecular design》2014,28(3):245-257
The correct representation of solute-water interactions is essential for the accurate simulation of most biological phenomena. Several highly accurate quantum methods are available to deal with solvation by using both implicit and explicit solvents. So far, however, most evaluations of those methods were based on a single conformation, which neglects solute entropy. Here, we present the first test of a novel approach to determine hydration free energies that uses molecular mechanics (MM) to sample phase space and quantum mechanics (QM) to evaluate the potential energies. Free energies are determined by using re-weighting with the Non-Boltzmann Bennett (NBB) method. In this context, the method is referred to as QM-NBB. Based on snapshots from MM sampling and accounting for their correct Boltzmann weight, it is possible to obtain hydration free energies that incorporate the effect of solute entropy. We evaluate the performance of several QM implicit solvent models, as well as explicit solvent QM/MM for the blind subset of the SAMPL4 hydration free energy challenge. While classical free energy simulations with molecular dynamics give root mean square deviations (RMSD) of 2.8 and 2.3 kcal/mol, the hybrid approach yields an improved RMSD of 1.6 kcal/mol. By selecting an appropriate functional and basis set, the RMSD can be reduced to 1 kcal/mol for calculations based on a single conformation. Results for a selected set of challenging molecules imply that this RMSD can be further reduced by using NBB to reweight MM trajectories with the SMD implicit solvent model. 相似文献
11.
Treating entropy and conformational changes in implicit solvent simulations of small molecules 总被引:1,自引:0,他引:1
Implicit solvent models are increasingly popular for estimating aqueous solvation (hydration) free energies in molecular simulations and other applications. In many cases, parameters for these models are derived to reproduce experimental values for small molecule hydration free energies. Often, these hydration free energies are computed for a single solute conformation, neglecting solute conformational changes upon solvation. Here, we incorporate these effects using alchemical free energy methods. We find significant errors when hydration free energies are estimated using only a single solute conformation, even for relatively small, simple, rigid solutes. For example, we find conformational entropy (TDeltaS) changes of up to 2.3 kcal/mol upon hydration. Interestingly, these changes in conformational entropy correlate poorly (R2 = 0.03) with the number of rotatable bonds. The present study illustrates that implicit solvent modeling can be improved by eliminating the approximation that solutes are rigid. 相似文献
12.
13.
We have studied the solvation of uranyl, UO(2)(2+), and the reduced species UO(OH)(2+) and U(OH)(2)(2+) systematically using three levels of approximation: direct application of a continuum model (M1); explicit quantum-chemical treatment of the first hydration sphere (M2); a combined quantum-chemical/continuum model approach (M3). We have optimized complexes with varying numbers of aquo ligands (n = 4-6) and compared their free energies of solvation. Models M1 and M2 have been found to recover the solvation energy only partially, underestimating it by approximately 100 kcal/mol or more. With our best model M3, the calculated hydration free energy Delta(h)G degrees of UO(2)(2+) is about -420 kcal/mol, which shifts to about -370 kcal/mol when corrected for the expected error of the model. This value agrees well with the experimentally determined interval, -437 kcal/mol < Delta(h)G degrees < -318 kcal/mol. Complexes with 5 and 6 aquo ligands have been found to be about equally favored with models M2 and M3. The same solvation models have been applied to a two-step reduction of UO(2)(2+) by water, previously theoretically studied in the gas phase. Our results show that the solvation contribution to the reaction free energy, about 60 kcal/mol, dominates the endoergicity of the reduction. 相似文献
14.
Implicit solvent models are powerful tools in accounting for the aqueous environment at a fraction of the computational expense of explicit solvent representations. Here, we compare the ability of common implicit solvent models (TC, OBC, OBC2, GBMV, GBMV2, GBSW, GBSW/MS, GBSW/MS2 and FACTS) to reproduce experimental absolute hydration free energies for a series of 499 small neutral molecules that are modeled using AMBER/GAFF parameters and AM1-BCC charges. Given optimized surface tension coefficients for scaling the surface area term in the nonpolar contribution, most implicit solvent models demonstrate reasonable agreement with extensive explicit solvent simulations (average difference 1.0-1.7 kcal/mol and R(2)=0.81-0.91) and with experimental hydration free energies (average unsigned errors=1.1-1.4 kcal/mol and R(2)=0.66-0.81). Chemical classes of compounds are identified that need further optimization of their ligand force field parameters and others that require improvement in the physical parameters of the implicit solvent models themselves. More sophisticated nonpolar models are also likely necessary to more effectively represent the underlying physics of solvation and take the quality of hydration free energies estimated from implicit solvent models to the next level. 相似文献
15.
16.
Naik PK Chatterji BP Vangapandu SN Aneja R Chandra R Kanteveri S Joshi HC 《Journal of computer-aided molecular design》2011,25(5):443-454
Noscapine and its derivatives are important microtubule-interfering agents shown to have potent anti-tumor activity. The binding
free energies (ΔG
bind) of noscapinoids computed using linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation
model were in agreement with the experimental ΔG
bind with average root mean square error of 0.082 kcal/mol. This LIE–SGB model guided us in designing a novel derivative of noscapine,
amino-noscapine [(S)-3-((R)-9-amino-4-methoxy-6-methyl-5,6,7,8-tetrahydro [1, 3] dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxy isobenzo-furan-1(3H)-one] that has higher tubulin binding activity (predicted ΔG
bind = −6.438 kcal/mol and experimental ΔG
bind = −6.628 kcal/mol) than noscapine, but does not significantly change the total extent of the tubulin subunit/polymer ratio.
The modes of interaction of amino-noscapine with the binding pocket of tubulin involved three hydrogen bonds and are distinct
compared to noscapine which involved only one hydrogen bond. Also the patterns of non-bonded interactions are albeit different
between both the lignads. The ‘blind docking’ approach (docking of ligand with different binding sites of a protein and their
evaluations) as well as the reasonable accuracy of calculating ΔG
bind using LIE–SGB model constitutes the first evidence that this class of compounds binds to tubulin at a site overlapping with
colchicine-binding site or close to it. Our results revealed that amino-noscapine has better anti-tumor activity than noscapine. 相似文献
17.
Mobley DL Baker JR Barber AE Fennell CJ Dill KA 《The journal of physical chemistry. B》2008,112(8):2405-2414
We study the solvation of polar molecules in water. The center of water's dipole moment is offset from its steric center. In common water models, the Lennard-Jones center is closer to the negatively charged oxygen than to the positively charged hydrogens. This asymmetry of water's charge sites leads to different hydration free energies of positive versus negative ions of the same size. Here, we explore these hydration effects for some hypothetical neutral solutes, and two real solutes, with molecular dynamics simulations using several different water models. We find that, like ions, polar solutes are solvated differently in water depending on the sign of the partial charges. Solutes having a large negative charge balancing diffuse positive charges are preferentially solvated relative to those having a large positive charge balancing diffuse negative charges. Asymmetries in hydration free energies can be as large as 10 kcal/mol for neutral benzene-sized solutes. These asymmetries are mainly enthalpic, arising primarily from the first solvation shell water structure. Such effects are not readily captured by implicit solvent models, which respond symmetrically with respect to charge. 相似文献
18.
Mütesir Temel Omer Tayfuroglu Abdulkadir Kocak 《Journal of computational chemistry》2023,44(4):559-569
Here, we investigate the performance of “Accurate NeurAl networK engINe for Molecular Energies” (ANI), trained on small organic compounds, on bulk systems including non-covalent interactions and applicability to estimate solvation (hydration) free energies using the interaction between the ligand and explicit solvent (water) from single-step MD simulations. The method is adopted from ANI using the Atomic Simulation Environment (ASE) and predicts the non-covalent interaction energies at the accuracy of wb97x/6-31G(d) level by a simple linear scaling for the conformations sampled by molecular dynamics (MD) simulations of ligand-n(H2O) systems. For the first time, we test ANI potentials' abilities to reproduce solvation free energies using linear interaction energy (LIE) formulism by modifying the original LIE equation. Our results on ~250 different complexes show that the method can be accurate and have a correlation of R2 = 0.88–0.89 (MAE <1.0 kcal/mol) to the experimental solvation free energies, outperforming current end-state methods. Moreover, it is competitive to other conventional free energy methods such as FEP and BAR with 15-20 × fold reduced computational cost. 相似文献
19.
Asger Halkier Henrik Koch Poul Jørgensen Ove Christiansen Ida M. Beck Nielsen Trygve Helgaker 《Theoretical chemistry accounts》1997,97(1-4):150-157
A systematic, high-level ab initio investigation of the water dimer has been performed. The oxygen-oxygen bond distance has
been estimated to be around 2.90 ?, about 0.05 ? shorter than the experimentally estimated distance, challenging the accuracy
of the latter. The interaction energy has been obtained at −5.0±0.1 kcal/mol, which compares favourably with the experimentally
estimated value of −5.4±0.7 kcal/mol. The importance of employing basis sets that include diffuse functions in correlated
calculations on hydrogen-bonded systems is confirmed. In correlated calculations on the water dimer and the hydrogen fluoride
dimer, the counterpoise-corrected interaction energies converge considerably slower towards the basis set limit than do the
uncorrected energies, provided that the correlation-consistent basis sets are augmented with diffuse functions.
Received: 12 February 1997 / Accepted: 5 June 1997 相似文献
20.
Raphael F. Ribeiro Aleksandr V. Marenich Christopher J. Cramer Donald G. Truhlar 《Journal of computer-aided molecular design》2010,24(4):317-333
We applied the solvation models SM8, SM8AD, and SMD in combination with the Minnesota M06-2X density functional to predict
vacuum-water transfer free energies (Task 1) and tautomeric ratios in aqueous solution (Task 2) for the SAMPL2 test set. The
bulk-electrostatic contribution to the free energy of solvation is treated as follows: SM8 employs the generalized Born model
with the Coulomb field approximation, SM8AD employs the generalized Born approximation with asymmetric descreening, and SMD
solves the nonhomogeneous Poisson equation. The non-bulk-electrostatic contribution arising from short-range interactions
between the solute and solvent molecules in the first solvation shell is treated as a sum of terms that are products of geometry-dependent
atomic surface tensions and solvent-accessible surface areas of the individual atoms of the solute. On average, three models
tested in the present work perform similarly. In particular, we achieved mean unsigned errors of 1.3 (SM8), 2.0 (SM8AD), and
2.6 kcal/mol (SMD) for the aqueous free energies of 30 out of 31 compounds with known reference data involved in Task 1 and
mean unsigned errors of 2.7 (SM8), 1.8 (SM8AD), and 2.4 kcal/mol (SMD) in the free energy differences (tautomeric ratios)
for 21 tautomeric pairs in aqueous solution involved in Task 2. 相似文献