Testing and Optimizing the Drude Polarizable Force Field for Blocked Amino Acids Based on High-Level Quantum-Mechanical Energy Surfaces

2022 ◽  
pp. 1-9
Author(s):  
Jinfeng Chen ◽  
Gerhard König
Keyword(s):  
Amino Acids ◽  
Force Field ◽  
Energy Surface ◽  
Mechanical Energy ◽  
Quantum Mechanical ◽  
Polarizable Force Field ◽  
Conformational Substates ◽  
Reorganization Energies ◽  
High Level ◽  
Energy Surfaces

The correct reproduction of conformational substates of amino acids was tested for the CHARMM Drude polarizable force field. This was achieved by evaluating the reorganization energies for all low lying energy minima occurring in all 15 neutral blocked amino acids on a quantum-mechanical (QM) energy surface at the MP2/cc-pVDZ level. The results indicate that the bonded parameters of the N-acetyl (ACE) and N-Methylamide (CT3) blocking groups lead to significant discrepancies. A reparametrization of five bond angles significantly improved the agreement with the QM energy surface. The corrected Drude force field exhibits almost the same average reorganization energies relative to the MP2 energy surface as the AM1 and PM3 semi-empirical methods.

scholarly journals On the faithfulness of molecular mechanics representations of proteins towards quantum-mechanical energy surfaces

2020 ◽  
Vol 10 (6) ◽  
pp. 20190121
Author(s):  
Gerhard König ◽  
Sereina Riniker
Keyword(s):  
Amino Acids ◽  
Force Field ◽  
Molecular Mechanics ◽  
Force Fields ◽  
Mechanical Energy ◽  
Reorganization Energy ◽  
Quantum Mechanical ◽  
Energy Minimum ◽  
Structural Reorganization ◽  
Reorganization Energies

Force fields based on molecular mechanics (MM) are the main computational tool to study the relationship between protein structure and function at the molecular level. To validate the quality of such force fields, high-level quantum-mechanical (QM) data are employed to test their capability to reproduce the features of all major conformational substates of a series of blocked amino acids. The phase-space overlap between MM and QM is quantified in terms of the average structural reorganization energies over all energy minima. Here, the structural reorganization energy is the MM potential-energy difference between the structure of the respective QM energy minimum and the structure of the closest MM energy minimum. Thus, it serves as a measure for the relative probability of visiting the QM minimum during an MM simulation. We evaluate variants of the AMBER, CHARMM, GROMOS and OPLS biomolecular force fields. In addition, the two blocked amino acids alanine and serine are used to demonstrate the dependence of the measured agreement on the QM method, the phase, and the conformational preferences. Blocked serine serves as an example to discuss possible improvements of the force fields, such as including polarization with Drude particles, or using tailored force fields. The results show that none of the evaluated force fields satisfactorily reproduces all energy minima. By decomposing the average structural reorganization energies in terms of individual energy terms, we can further assess the individual weaknesses of the parametrization strategies of each force field. The dominant problem for most force fields appears to be the van der Waals parameters, followed to a lesser degree by dihedral and bonded terms. Our results show that performing a simple QM energy optimization from an MM-optimized structure can be a first test of the validity of a force field for a particular target molecule.

scholarly journals Current Status of AMOEBA–IL: A Multipolar/Polarizable Force Field for Ionic Liquids

2020 ◽  
Vol 21 (3) ◽  
pp. 697
Author(s):  
Erik Antonio Vázquez-Montelongo ◽  
José Enrique Vázquez-Cervantes ◽  
G. Andrés Cisneros
Keyword(s):  
Ionic Liquid ◽  
Force Field ◽  
Decomposition Analysis ◽  
Lanthanide Ions ◽  
Current Status ◽  
Energy Decomposition Analysis ◽  
Quantum Mechanical ◽  
Exchange Reactions ◽  
Polarizable Force Field ◽  
Liquid Systems

Computational simulations of ionic liquid solutions have become a useful tool to investigate various physical, chemical and catalytic properties of systems involving these solvents. Classical molecular dynamics and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations of IL systems have provided significant insights at the atomic level. Here, we present a review of the development and application of the multipolar and polarizable force field AMOEBA for ionic liquid systems, termed AMOEBA–IL. The parametrization approach for AMOEBA–IL relies on the reproduction of total quantum mechanical (QM) intermolecular interaction energies and QM energy decomposition analysis. This approach has been used to develop parameters for imidazolium– and pyrrolidinium–based ILs coupled with various inorganic anions. AMOEBA–IL has been used to investigate and predict the properties of a variety of systems including neat ILs and IL mixtures, water exchange reactions on lanthanide ions in IL mixtures, IL–based liquid–liquid extraction, and effects of ILs on an aniline protection reaction.

scholarly journals A quantum mechanical polarizable force field for biomolecular interactions

2005 ◽  
Vol 102 (22) ◽  
pp. 7829-7834 ◽  
Author(s):  
A. G. Donchev ◽  
V. D. Ozrin ◽  
M. V. Subbotin ◽  
O. V. Tarasov ◽  
V. I. Tarasov
Keyword(s):  
Force Field ◽  
Biomolecular Interactions ◽  
Quantum Mechanical ◽  
Polarizable Force Field

scholarly journals Benchmarking Force Field and the ANI Neural Network Potentials for the Torsional Potential Energy Surface of Biaryl Drug Fragments

2020 ◽  
Author(s):  
Shae-Lynn Lahey ◽  
Từ Nguyễn Thiên Phúc ◽  
Christopher Rowley
Keyword(s):  
Neural Network ◽  
Potential Energy ◽  
Force Field ◽  
Potential Energy Surfaces ◽  
Md Simulations ◽  
Absolute Deviation ◽  
Torsional Potential ◽  
The Mean ◽  
High Level ◽  
Energy Surfaces

Many drug molecules contain biaryl fragments, resulting in a torsional barrier corresponding to rotation around the bond linking the aryls. The potential energy surfaces of these torsions vary significantly due to steric and electronic effects, ultimately affecting the relative stability of the molecular conformations in the protein-bound and solution states. Simulations of protein--ligand binding require accurate computational models to represent the intramolecular interactions to provide accurate predictions of the structure and dynamics of binding. In this paper, we compare four force fields (Generalized AMBER Force Field (GAFF), Open Force Field (OpenFF), CHARMM General Force Field (CGenFF), Optimized Potentials for Liquid Simulations (OPLS)) and two neural network potentials (ANI-2x, ANI-1ccx) in their ability to predict the torsional potential energy surfaces of 88 biaryls extracted from drug fragments. The mean of the absolute deviation over the full PES (MADF) and the mean absolute deviation of the torsion rotational barrier height (MADB) relative to high-level ab initio reference data was used as a measure of accuracy. In comparison to high-level ab-initio data, ANI-1ccx was most accurate for predicting the barrier height (MADF: 0.5~kcal/mol, MADB:~0.8~kcal/mol), followed closely by ANI-2x (MADF: 0.5~kcal/mol, MADB:~1.0~kcal/mol), then CGenFF (MADF: 0.8~kcal/mol, MADB: 1.3~kcal/mol), OpenFF (MADF: 1.5~kcal/mol, MADB: 1.4~kcal/mol), GAFF (MADF: 1.2~kcal/mol, MADB: 2.6~kcal/mol), and finally OPLS (MADF: 1.5~kcal/mol, MADB: 2.8~kcal/mol). Significantly, the NNPs are systematically more accurate and more reliable than any of the force fields. As a practical example, the neural network potential/molecular mechanics (NNP/MM) method was used to simulate the isomerization of ozanimod, a drug used for multiple sclerosis. Multi-nanosecond molecular dynamics (MD) simulations in an explicit aqueous solvent were performed, as well as umbrella sampling and adaptive biasing force enhanced sampling techniques. These theories predicted a rate of isomerization of $4.30 \times 10^{-1}$ ns$^{-1}$, which is consistent with direct MD simulations.

scholarly journals Combining EXAFS and Computer Simulations to Refine the Structural Description of Actinyls in Water

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5250
Author(s):  
Sergio Pérez-Conesa ◽  
José M. Martínez ◽  
Rafael R. Pappalardo ◽  
Enrique Sánchez Marcos
Keyword(s):  
Potential Energy ◽  
Potential Energy Surface ◽  
Force Field ◽  
Electron Correlation ◽  
Energy Surface ◽  
Open Shell ◽  
Complex Signal ◽  
Quantum Mechanical ◽  
Structural Description ◽  
Exafs Spectra

EXAFS spectroscopy is one of the most used techniques to solve the structure of actinoid solutions. In this work a systematic analysis of the EXAFS spectra of four actinyl cations, [UO2]2+, [NpO2]2+, [NpO2]+ and [PuO2]2+ has been carried out by comparing experimental results with theoretical spectra. These were obtained by averaging individual contributions from snapshots taken from classical Molecular Dynamics simulations which employed a recently developed [AnO2]2+/+ –H2O force field based on the hydrated ion model using a quantum-mechanical (B3LYP) potential energy surface. Analysis of the complex EXAFS signal shows that both An-Oyl and An-OW single scattering paths as well as multiple scattering ones involving [AnO2]+/2+ molecular cation and first-shell water molecules are mixed up all together to produce a very complex signal. Simulated EXAFS from the B3LYP force field are in reasonable agreement for some of the cases studied, although the k= 6–8 Å−1 region is hard to be reproduced theoretically. Except uranyl, all studied actinyls are open-shell electron configurations, therefore it has been investigated how simulated EXAFS spectra are affected by minute changes of An-O bond distances produced by the inclusion of static and dynamic electron correlation in the quantum mechanical calculations. A [NpO2]+−H2O force field based on a NEVPT2 potential energy surface has been developed. The small structural changes incorporated by the electron correlation on the actinyl aqua ion geometry, typically smaller than 0.07 Å, leads to improve the simulated spectrum with respect to that obtained from the B3LYP force field. For the other open-shell actinyls, [NpO2]2+ and [PuO2]2+, a simplified strategy has been adopted to improve the simulated EXAFS spectrum. It is computed taking as reference structure the NEVPT2 optimized geometry and including the DW factors of their corresponding MD simulations employing the B3LYP force field. A better agreement between the experimental and the simulated EXAFS spectra is found, confirming the a priori guess that the inclusion of dynamic and static correlation refine the structural description of the open-shell actinyl aqua ions.

Benchmarking Force Field and the ANI Neural Network Potentials for the Torsional Potential Energy Surface of Biaryl Drug Fragments

2020 ◽  
Author(s):  
Shae-Lynn Lahey ◽  
Từ Nguyễn Thiên Phúc ◽  
Christopher Rowley
Keyword(s):  
Neural Network ◽  
Potential Energy ◽  
Force Field ◽  
Potential Energy Surfaces ◽  
Md Simulations ◽  
Absolute Deviation ◽  
Torsional Potential ◽  
The Mean ◽  
High Level ◽  
Energy Surfaces

Many drug molecules contain biaryl fragments, resulting in a torsional barrier corresponding to rotation around the bond linking the aryls. The potential energy surfaces of these torsions vary significantly due to steric and electronic effects, ultimately affecting the relative stability of the molecular conformations in the protein-bound and solution states. Simulations of protein--ligand binding require accurate computational models to represent the intramolecular interactions to provide accurate predictions of the structure and dynamics of binding. In this paper, we compare four force fields (Generalized AMBER Force Field (GAFF), Open Force Field (OpenFF), CHARMM General Force Field (CGenFF), Optimized Potentials for Liquid Simulations (OPLS)) and two neural network potentials (ANI-2x, ANI-1ccx) in their ability to predict the torsional potential energy surfaces of 88 biaryls extracted from drug fragments. The mean of the absolute deviation over the full PES (MADF) and the mean absolute deviation of the torsion rotational barrier height (MADB) relative to high-level ab initio reference data was used as a measure of accuracy. In comparison to high-level ab-initio data, ANI-1ccx was most accurate for predicting the barrier height (MADF: 0.5~kcal/mol, MADB:~0.8~kcal/mol), followed closely by ANI-2x (MADF: 0.5~kcal/mol, MADB:~1.0~kcal/mol), then CGenFF (MADF: 0.8~kcal/mol, MADB: 1.3~kcal/mol), OpenFF (MADF: 1.5~kcal/mol, MADB: 1.4~kcal/mol), GAFF (MADF: 1.2~kcal/mol, MADB: 2.6~kcal/mol), and finally OPLS (MADF: 1.5~kcal/mol, MADB: 2.8~kcal/mol). Significantly, the NNPs are systematically more accurate and more reliable than any of the force fields. As a practical example, the neural network potential/molecular mechanics (NNP/MM) method was used to simulate the isomerization of ozanimod, a drug used for multiple sclerosis. Multi-nanosecond molecular dynamics (MD) simulations in an explicit aqueous solvent were performed, as well as umbrella sampling and adaptive biasing force enhanced sampling techniques. These theories predicted a rate of isomerization of $4.30 \times 10^{-1}$ ns$^{-1}$, which is consistent with direct MD simulations.

Induced polarization restricts the conformational distribution of a light-harvesting molecular triad in the ground state

2017 ◽  
Vol 19 (34) ◽  
pp. 22969-22980 ◽  
Author(s):  
Oleg N. Starovoytov ◽  
Pengzhi Zhang ◽  
Piotr Cieplak ◽  
Margaret S. Cheung
Keyword(s):  
Force Field ◽  
Ground State ◽  
Energy Surface ◽  
Light Harvesting ◽  
Induced Polarization ◽  
Conformational Space ◽  
Chemical Bonds ◽  
Free Energy Surface ◽  
Polarizable Force Field ◽  
Conformational Distribution

Free energy surface of the light-harvesting triad employing a non-polarizable force field (NFF) and a polarizable force field (PFF) shows that induced polarization limits the motion of rotation about chemical bonds as well as bending at the porphyrin, which are prominent using the NFF, thus limiting the conformational space of the triad.

scholarly journals Mechanistic Analysis of Light-Driven Overcrowded Alkene-Based Molecular Motors by Multiscale Molecular Simulations

2020 ◽  
Author(s):  
Mudong Feng ◽  
Michael K. Gilson
Keyword(s):  
Molecular Motors ◽  
Performance Metrics ◽  
Multiple Scales ◽  
Mechanical Energy ◽  
Md Simulations ◽  
Maximal Power Output ◽  
Conformational Substates ◽  
Rotation Rates ◽  
Full Rotation ◽  
Energy Surfaces

We analyze light-driven overcrowded alkene-based molecular motors, an intriguing class of small molecules that have the potential to generate MHz-scale rotation rates. The full rotation process is simulated at multiple scales by combining quantum surface-hopping molecular dynamics (MD) simulations for the photoisomerization step with classical MD simulations for the thermal helix inversion step. A Markov state analysis resolves conformational substates, their interconversion kinetics, and their roles in the motor’s rotation process. Furthermore, motor performance metrics, including rotation rate and maximal power output, are computed to validate computations against experimental measurements and to inform future designs. Lastly, we find that to correctly model these motors, the force field must be optimized by fitting selected parameters to reference quantum mechanical energy surfaces. Overall, our simulations yield encouraging agreement with experimental observables such as rotation rates, and provide mechanistic insights that may help future designs.

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