scholarly journals Non-equilibrium approach for binding free energies in cyclodextrins in SAMPL7: force fields and software

2020 ◽  
Author(s):  
Yuriy Khalak ◽  
Gary Tresadern ◽  
Bert L. de Groot ◽  
Vytautas Gapsys
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Force Fields ◽  
Simulation Software ◽  
Energy Estimates ◽  
Energy Calculation ◽  
Free Energies ◽  
Guest Molecules ◽  
Software Packages ◽  
Non Equilibrium

AbstractIn the current work we report on our participation in the SAMPL7 challenge calculating absolute free energies of the host–guest systems, where 2 guest molecules were probed against 9 hosts-cyclodextrin and its derivatives. Our submission was based on the non-equilibrium free energy calculation protocol utilizing an averaged consensus result from two force fields (GAFF and CGenFF). The submitted prediction achieved accuracy of $${1.38}\,\hbox {kcal}/\hbox {mol}$$ 1.38 kcal / mol in terms of the unsigned error averaged over the whole dataset. Subsequently, we further report on the underlying reasons for discrepancies between our calculations and another submission to the SAMPL7 challenge which employed a similar methodology, but disparate ligand and water force fields. As a result we have uncovered a number of issues in the dihedral parameter definition of the GAFF 2 force field. In addition, we identified particular cases in the molecular topologies where different software packages had a different interpretation of the same force field. This latter observation might be of particular relevance for systematic comparisons of molecular simulation software packages. The aforementioned factors have an influence on the final free energy estimates and need to be considered when performing alchemical calculations.

scholarly journals Comparing Dimerization Free Energies and Binding Modes of Small Aromatic Molecules with Different Force Fields

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6069
Author(s):  
Ilias Patmanidis ◽  
Riccardo Alessandri ◽  
Alex H. de de Vries ◽  
Siewert J. Marrink
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Force Fields ◽  
Supramolecular Assembly ◽  
Model Systems ◽  
Binding Modes ◽  
Free Energies ◽  
Care Needs ◽  
Strength Of Interaction ◽  
Dynamics Simulations

Dimerization free energies are fundamental quantities that describe the strength of interaction of different molecules. Obtaining accurate experimental values for small molecules and disentangling the conformations that contribute most to the binding can be extremely difficult, due to the size of the systems and the small energy differences. In many cases, one has to resort to computational methods to calculate such properties. In this work, we used molecular dynamics simulations in conjunction with metadynamics to calculate the free energy of dimerization of small aromatic rings, and compared three models from popular online servers for atomistic force fields, namely G54a7, CHARMM36 and OPLS. We show that, regardless of the force field, the profiles for the dimerization free energy of these compounds are very similar. However, significant care needs to be taken when studying larger molecules, since the deviations from the trends increase with the size of the molecules, resulting in force field dependent preferred stacking modes; for example, in the cases of pyrene and tetracene. Our results provide a useful background study for using topology builders to model systems which rely on stacking of aromatic moieties, and are relevant in areas ranging from drug design to supramolecular assembly.

scholarly journals Expanded Ensemble Methods Can Be Used to Accurately Predict Protein-Ligand Relative Binding Free Energies

2021 ◽  
Author(s):  
Si Zhang ◽  
David Hahn ◽  
Michael R. Shirts ◽  
Vincent Voelz
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Ensemble Methods ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Free Energies ◽  
Relative Binding ◽  
Alchemical Free Energy ◽  
Binding Free Energies ◽  
Expanded Ensemble

<p>Alchemical free energy methods have become indispensable in computational drug discovery for their ability to calculate highly accurate estimates of protein-ligand affinities. Expanded ensemble (EE) methods, which involve single simulations visiting all of the alchemical intermediates, have some key advantages for alchemical free energy calculation. However, there have been relatively few examples published in the literature of using expanded ensemble simulations for free energies of protein-ligand binding. In this paper, as a test of expanded ensemble methods, we computed relative binding free energies using the Open Force Field Initiative force field (codename “Parsley”) for twenty-four pairs of Tyk2 inhibitors derived from a congeneric series of 16 compounds. The EE predictions agree well with the experimental values (RMSE of 0.94 ± 0.13 kcal mol<sup>−1</sup> and MUE of 0.75 ± 0.12 kcal mol<sup>−1</sup>). We find that while increasing the number of alchemical intermediates can improve the phase space overlap, faster convergence can be obtained with fewer intermediates, as long as the acceptance rates are sufficient. We find that convergence can be improved using more aggressive updating of the biases, and that estimates can be improved by performing multiple independent EE calculations. This work demonstrates that EE is a viable option for alchemical free energy calculation. We discuss the implications of these findings for rational drug design, as well as future directions for improvement.</p>

scholarly journals Expanded Ensemble Methods Can Be Used to Accurately Predict Protein-Ligand Relative Binding Free Energies

2021 ◽  
Author(s):  
Si Zhang ◽  
David Hahn ◽  
Michael R. Shirts ◽  
Vincent Voelz
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Ensemble Methods ◽  
Free Energy Calculation ◽  
Energy Calculation ◽  
Free Energies ◽  
Relative Binding ◽  
Alchemical Free Energy ◽  
Binding Free Energies ◽  
Expanded Ensemble

<p>Alchemical free energy methods have become indispensable in computational drug discovery for their ability to calculate highly accurate estimates of protein-ligand affinities. Expanded ensemble (EE) methods, which involve single simulations visiting all of the alchemical intermediates, have some key advantages for alchemical free energy calculation. However, there have been relatively few examples published in the literature of using expanded ensemble simulations for free energies of protein-ligand binding. In this paper, as a test of expanded ensemble methods, we computed relative binding free energies using the Open Force Field Initiative force field (codename “Parsley”) for twenty-four pairs of Tyk2 inhibitors derived from a congeneric series of 16 compounds. The EE predictions agree well with the experimental values (RMSE of 0.94 ± 0.13 kcal mol<sup>−1</sup> and MUE of 0.75 ± 0.12 kcal mol<sup>−1</sup>). We find that while increasing the number of alchemical intermediates can improve the phase space overlap, faster convergence can be obtained with fewer intermediates, as long as the acceptance rates are sufficient. We find that convergence can be improved using more aggressive updating of the biases, and that estimates can be improved by performing multiple independent EE calculations. This work demonstrates that EE is a viable option for alchemical free energy calculation. We discuss the implications of these findings for rational drug design, as well as future directions for improvement.</p>

Hydration Free Energies of Organic Molecules in the FreeSolv Database Calculated with Polarized Atom In Molecules Atomic Charges and the GAFF Force Field.

2018 ◽  
Author(s):  
Maximiliano Riquelme ◽  
Alejandro Lara ◽  
David L. Mobley ◽  
Toon Vestraelen ◽  
Adelio R Matamala ◽  
...  
Keyword(s):  
Force Field ◽  
Functional Groups ◽  
Electrostatic Interactions ◽  
Organic Molecules ◽  
Force Fields ◽  
Chemical Elements ◽  
Atomic Charges ◽  
Free Energies ◽  
Molecular Systems ◽  
Solvent Model

<div>Computer simulations of bio-molecular systems often use force fields, which are combinations of simple empirical atom-based functions to describe the molecular interactions. Even though polarizable force fields give a more detailed description of intermolecular interactions, nonpolarizable force fields, developed several decades ago, are often still preferred because of their reduced computation cost. Electrostatic interactions play a major role in bio-molecular systems and are therein described by atomic point charges.</div><div>In this work, we address the performance of different atomic charges to reproduce experimental hydration free energies in the FreeSolv database in combination with the GAFF force field. Atomic charges were calculated by two atoms-in-molecules approaches, Hirshfeld-I and Minimal Basis Iterative Stockholder (MBIS). To account for polarization effects, the charges were derived from the solute's electron density computed with an implicit solvent model and the energy required to polarize the solute was added to the free energy cycle. The calculated hydration free energies were analyzed with an error model, revealing systematic errors associated with specific functional groups or chemical elements. The best agreement with the experimental data is observed for the MBIS atomic charge method, including the solvent polarization, with a root mean square error of 2.0 kcal mol<sup>-1</sup> for the 613 organic molecules studied. The largest deviation was observed for phosphor-containing molecules and the molecules with amide, ester and amine functional groups.</div>

scholarly journals Adsorption of Amino Acids on Graphene: Assessment of Current Force Fields

2019 ◽  
Author(s):  
Siva Dasetty ◽  
John K. Barrows ◽  
Sapna Sarupria
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Force Field ◽  
Force Fields ◽  
Principal Component ◽  
Free Energies ◽  
Adsorbed State ◽  
Free Energy Of Adsorption ◽  
Density Based Clustering ◽  
Structural Preferences

<div> <div> <div> <p>We compare the free energies of adsorption (∆Aads) and the structural preferences of amino acids obtained using the force fields — Amberff99SB-ILDN/TIP3P, CHARMM36/modified-TIP3P, OPLS-AA/M/TIP3P, and Amber03w/TIP4P/2005. The amino acid–graphene interactions are favorable irrespective of the force field. While the magnitudes of ∆Aads differ between the force fields, the trends in the free energy of adsorption with amino acids are similar across the studied force fields. ∆Aads positively correlates with amino acid–graphene and negatively correlates with graphene–water interaction energies. Using a combination of principal component analysis and density-based clustering technique, we grouped the structures observed in the graphene adsorbed state. The resulting population of clusters, and the conformation in each cluster indicate that the structures of the amino acid in the graphene adsorbed state vary across force fields. The differences in the conformations of amino acids are more severe in the graphene adsorbed state compared to the bulk state for all the force fields. Our findings suggest that while the thermodynamics of adsorption of proteins and peptides would be described consistently across different force fields, the structural preferences of peptides and proteins on graphene will be force field dependent. </p> </div> </div> </div>

scholarly journals Reproducibility of Free Energy Calculations across Different Molecular Simulation Software Packages

2018 ◽  
Vol 14 (11) ◽  
pp. 5567-5582 ◽  
Author(s):  
Hannes H. Loeffler ◽  
Stefano Bosisio ◽  
Guilherme Duarte Ramos Matos ◽  
Donghyuk Suh ◽  
Benoit Roux ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Simulation ◽  
Simulation Software ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Software Packages

scholarly journals GAFF/IPolQ-Mod+LJ-Fit: Optimized force field parameters for solvation free energy predictions

ADMET & DMPK ◽  
2020 ◽  
Author(s):  
Andreas Mecklenfeld ◽  
Gabriele Raabe
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Fluid Phase ◽  
Solvation Free Energy ◽  
Rational Drug Design ◽  
Phase Behaviour ◽  
Liquid Density ◽  
Free Energies ◽  
Implicit Representation ◽  
Amber Force Field

<p class="ADMETabstracttext">Rational drug design featuring explicit solubility considerations can greatly benefit from molecular dynamics simulations, as they allow for the prediction of the Gibbs free energy of solvation and thus relative solubilities. In our previous work (A. Mecklenfeld, G. Raabe. J. Chem. Theory Comput. <strong>13 </strong>no. 12 (2017) 6266–6274), we have compared solvation free energy results obtained with the General Amber Force Field (GAFF) and its default restrained electrostatic potential (RESP) partial charges to those obtained by modified implicitly polarized charges (IPolQ-Mod) for an implicit representation of impactful polarization effects. In this work, we have adapted Lennard-Jones parameters for GAFF atom types in combination with IPolQ-Mod to further improve the accuracies of solvation free energy and liquid density predictions. We thereby focus on prominent atom types in common drugs. For the refitting, 357 respectively 384 systems were considered for free energies and densities and validation was performed for 142 free energies and 100 densities of binary mixtures. By the in-depth comparison of simulation results for default GAFF, GAFF with IPolQ-Mod and our new set of parameters, which we label GAFF/IPolQ-Mod+LJ-Fit, we can clearly highlight the improvements of our new model for the description of both relative solubilities and fluid phase behaviour.</p>

scholarly journals Binding thermodynamics of host-guest systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initiative

2019 ◽  
Author(s):  
David Slochower ◽  
Niel Henriksen ◽  
Lee-Ping Wang ◽  
John Chodera ◽  
David Mobley ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Force Field ◽  
Small Molecule ◽  
Force Fields ◽  
Free Energy Calculations ◽  
Model Systems ◽  
Conformational Space ◽  
Free Energies ◽  
Binding Thermodynamics ◽  
Binding Free Energies

<div><div><div><p>Designing ligands that bind their target biomolecules with high affinity and specificity is a key step in small- molecule drug discovery, but accurately predicting protein-ligand binding free energies remains challenging. Key sources of errors in the calculations include inadequate sampling of conformational space, ambiguous protonation states, and errors in force fields. Noncovalent complexes between a host molecule with a binding cavity and a drug-like guest molecules have emerged as powerful model systems. As model systems, host-guest complexes reduce many of the errors in more complex protein-ligand binding systems, as their small size greatly facilitates conformational sampling, and one can choose systems that avoid ambiguities in protonation states. These features, combined with their ease of experimental characterization, make host-guest systems ideal model systems to test and ultimately optimize force fields in the context of binding thermodynamics calculations.</p><p><br></p><p>The Open Force Field Initiative aims to create a modern, open software infrastructure for automatically generating and assessing force fields using data sets. The first force field to arise out of this effort, named SMIRNOFF99Frosst, has approximately one tenth the number of parameters, in version 1.0.5, compared to typical general small molecule force fields, such as GAFF. Here, we evaluate the accuracy of this initial force field, using free energy calculations of 43 α and β-cyclodextrin host-guest pairs for which experimental thermodynamic data are available, and compare with matched calculations using two versions of GAFF. For all three force fields, we used TIP3P water and AM1-BCC charges. The calculations are performed using the attach-pull-release (APR) method as implemented in the open source package, pAPRika. For binding free energies, the root mean square error of the SMIRNOFF99Frosst calculations relative to experiment is 0.9 [0.7, 1.1] kcal/mol, while the corresponding results for GAFF 1.7 and GAFF 2.1 are 0.9 [0.7, 1.1] kcal/mol and 1.7 [1.5, 1.9] kcal/mol, respectively, with 95% confidence ranges in brackets. These results suggest that SMIRNOFF99Frosst performs competitively with existing small molecule force fields and is a parsimonious starting point for optimization.</p></div></div></div>

scholarly journals Reproducibility of Free Energy Calculations Across Different Molecular Simulation Software

2018 ◽  
Author(s):  
Hannes H. Loeffler ◽  
Stefano Bosisio ◽  
Guilherme Duarte Ramos Matos ◽  
Donghyuk Suh ◽  
Benoît Roux ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Simulation ◽  
Simulation Software ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Small Organic Molecules ◽  
Energy Calculations ◽  
Alchemical Free Energy ◽  
Attention To Detail ◽  
Alchemical Free Energy Calculations

<div> <div> <div> <p>Alchemical free energy calculations are an increasingly important modern simulation technique. Contemporary molecular simulation software such as AMBER, CHARMM, GROMACS and SOMD include support for the method. Implementation details vary among those codes but users expect reliability and reproducibility, i.e. for a given molec- ular model and set of forcefield parameters, comparable free energy should be obtained within statistical bounds regardless of the code used. Relative alchemical free energy (RAFE) simulation is increasingly used to support molecule discovery projects, yet the reproducibility of the methodology has been less well tested than its absolute counter- part. Here we present RAFE calculations of hydration free energies for a set of small organic molecules and demonstrate that free energies can be reproduced to within about 0.2 kcal/mol with aforementioned codes. Achieving this level of reproducibility requires considerable attention to detail and package–specific simulation protocols, and no uni- versally applicable protocol emerges. The benchmarks and protocols reported here should be useful for the community to validate new and future versions of software for free energy calculations.</p></div></div></div>

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