A Guide to the Continuous Constant pH Molecular Dynamics Methods in Amber and CHARMM [Article v1.0]

Henderson, Jack A.; Liu, Ruibin; Harris, Robert C.; Huang, Yandong; Oliveira, Vinícius Martins de; Shen, Jana

doi:10.33011/livecoms.4.1.1563

Cited by 23 publications

(27 citation statements)

References 100 publications

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“…2) is dynamically propagated on the same footing as θ . For carboxylic acids Asp and Glu which have two equivalent protonation sites (carboxyl oxygens), the model PMF function can be written as 9 42,49 where R 1 , …, R 6 are parameters that can be determined by one-dimensional fitting of the corresponding mean forces ( ∂U / ∂θ )| θx and ( ∂U / ∂θ x )| θ calculated using thermodynamic integration (TI) at different combinations of θ and θ x values. The detailed derivation and protocol are given in Ref.…”

Section: Methods and Implementationmentioning

confidence: 99%

“…The detailed derivation and protocol are given in Ref. 9,49 The model PMF function for His titration can be written as 9…”

Section: Potential Of Mean Force Functions For Model Titration the Li...mentioning

confidence: 99%

“…Detailed protocols for obtaining the parameters are given in Ref. 9,49 Finite-size corrections to the calculated pK a values for proteins. In our previous work, 11 we proposed a correction for the pK a 's calculated from the all-atom PME constant pH simulations under periodic boundary conditions.…”

Section: Potential Of Mean Force Functions For Model Titration the Li...mentioning

confidence: 99%

“…The detailed protocols are given in a recent tutorial. 49 As validation of the model parameters, titration simulations were conducted for the model peptides at independent pH conditions, which were placed at 0.5-pH intervals in the range of 2-5.5 for Asp, 2.5-6 for Glu, 4.5-8 for His, 6.5-10 for Cys, and 8-11.5 for Lys model peptides. The equilibration and production runs of the peptide systems followed the same protocols as the protein simulations (see latter discussion).…”

Section: Simulation Protocolsmentioning

confidence: 99%

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GPU-Accelerated All-atom Particle-Mesh Ewald Continuous Constant pH Molecular Dynamics in Amber

Harris

Liu

Oliveira

et al. 2022

Preprint

Self Cite

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Constant pH molecular dynamics (MD) simulations sample protonation states on the fly according to the conformational environment and user specified pH condition; however, the accuracy of most current applications is limited due to the use of implicit-solvent models or hybrid solvent scheme. Here we report the first GPU-accelerated implementation, parameterization, and validation of the all-atom continuous constant pH MD (CpHMD) method with particle-mesh Ewald (PME) electrostatics in the Amber22 pmemd.cuda engine. The titration parameters for Asp, Glu, His, Cys, and Lys were derived for the CHARMM c22 and Amber ff14sb and ff19sb force fields. We then evaluated the PME-CpHMD method using the asynchronous pH replica-exchange titration simulations with the c22 force field for six benchmark proteins, including BBL, hen egg white lysozyme (HEWL), staphylococcal nuclease (SNase), thioredoxin, ribonuclease A (RNaseA), and human muscle creatine kinase (HMCK). The root-mean-square deviation from the experimental pKa's of Asp, Glu, His, and Cys is 0.76 pH units, and the Pearson's correlation coefficient for the pKa shifts with respect to model values is 0.80. We demonstrated that a finite-size correction or much enlarged simulation box size can remove a systematic error of the calculated {\pka's} and improve agreement with experiment. Importantly, the simulations captured the relevant biology in several challenging cases, e.g., the titration order of the catalytic dyad Glu35/Asp52 in HEWL and the coupled residues Asp19/Asp21 in SNase, the large pKa upshift of the deeply buried catalytic Asp26 in thioredoxin, and the large {\pka} downshift of the deeply buried catalytic Cys283 in HMCK. We anticipate that PME-CpHMD will offer proper pH control to improve the accuracies of MD simulations and enable mechanistic studies of proton-coupled dynamical processes that are ubiquitous in biology but remain poorly understood due to the lack of experimental tools and limitation of current MD simulations.

show abstract

Section: Methods and Implementationmentioning

confidence: 99%

“…The detailed derivation and protocol are given in Ref. 9,49 The model PMF function for His titration can be written as 9…”

Section: Potential Of Mean Force Functions For Model Titration the Li...mentioning

confidence: 99%

Section: Potential Of Mean Force Functions For Model Titration the Li...mentioning

confidence: 99%

Section: Simulation Protocolsmentioning

confidence: 99%

See 2 more Smart Citations

GPU-Accelerated All-atom Particle-Mesh Ewald Continuous Constant pH Molecular Dynamics in Amber

Harris

Liu

Oliveira

et al. 2022

Preprint

Self Cite

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show abstract

“…The underlying variable θ x which is defined in analogy to θ (eq ) is dynamically propagated on the same footing as θ. For carboxylic acids Asp and Glu which have two equivalent protonation sites (carboxyl oxygens), the model PMF function can be written as ,, U normalA normals normalp / normalG normall normalu mod false( λ , x false) = false( R 1 λ 2 + R 2 λ + R 3 false) ( x + R 4 ) 2 + R 5 λ 2 + R 6 λ where R 1 , ..., R 6 are parameters that can be determined by one-dimensional fitting of the corresponding mean forces ( ∂ U / ∂ θ ) false| θ x and ( ∂U / ∂θ x )| θ calculated using thermodynamic integration (TI) at different combinations of θ and θ x values. The detailed derivation and protocol are given in refs and .…”

Section: Methods and Implementationmentioning

confidence: 99%

GPU-Accelerated All-Atom Particle-Mesh Ewald Continuous Constant pH Molecular Dynamics in Amber

Harris

Liu

Oliveira

et al. 2022

J. Chem. Theory Comput.

Self Cite

View full text Add to dashboard Cite

Constant pH molecular dynamics (MD) simulations sample protonation states on the fly according to the conformational environment and user specified pH conditions; however, the current accuracy is limited due to the use of implicitsolvent models or a hybrid solvent scheme. Here, we report the first GPU-accelerated implementation, parametrization, and validation of the all-atom continuous constant pH MD (CpHMD) method with particle-mesh Ewald (PME) electrostatics in the Amber22 pmemd.cuda engine. The titration parameters for Asp, Glu, His, Cys, and Lys were derived for the CHARMM c22 and Amber ff14sb and ff19sb force fields. We then evaluated the PME-CpHMD method using the asynchronous pH replicaexchange titration simulations with the c22 force field for six benchmark proteins, including BBL, hen egg white lysozyme (HEWL), staphylococcal nuclease (SNase), thioredoxin, ribonuclease A (RNaseA), and human muscle creatine kinase (HMCK). The root-mean-square deviation from the experimental pK a 's of Asp, Glu, His, and Cys is 0.76 pH units, and the Pearson's correlation coefficient for the pK a shifts with respect to model values is 0.80. We demonstrated that a finite-size correction or much enlarged simulation box size can remove a systematic error of the calculated pK a 's and improve agreement with experiment. Importantly, the simulations captured the relevant biology in several challenging cases, e.g., the titration order of the catalytic dyad Glu35/Asp52 in HEWL and the coupled residues Asp19/Asp21 in SNase, the large pK a upshift of the deeply buried catalytic Asp26 in thioredoxin, and the large pK a downshift of the deeply buried catalytic Cys283 in HMCK. We anticipate that PME-CpHMD will offer proper pH control to improve the accuracies of MD simulations and enable mechanistic studies of proton-coupled dynamical processes that are ubiquitous in biology but remain poorly understood due to the lack of experimental tools and limitation of current MD simulations.

show abstract

pH‐Dependent Assembly and Stability of Toll‐Like Receptor 3/dsRNA Signaling Complex: Insights from Constant pH Molecular Dynamics and Metadynamics Simulations

Li,

Shi,

Wang

et al. 2024

Advanced Science

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The pH‐dependent assembly of Toll‐like receptors (TLRs), which triggers a threshold‐like response, is a key principle in immune signaling. While crystallography has revealed the intricate structure of these assembly complexes, the mechanisms underlying their pH dependency remain unclear. Herein, constant pH simulations and metadynamics are employed to investigate the pH‐dependent assembly and stability of the TLR3/dsRNA signaling complex. The findings demonstrate that system pH regulates complex assembly and stability by modulating the protonation and charge states of histidines. Histidines in TLR3 act as pH‐dependent, positively charged binding sites that capture negatively charged dsRNA. Additionally, these histidines form a [H682⁺]—[E626⁻] dipole, facilitating the assembly of two TLR3 molecules into an antisymmetric dimer through dipole–dipole interactions. Surprisingly, TLR3 can shift the pKa values of key histidines from their model pKa of 6.5, increasing protonation likelihood and enhancing ligand binding. Notably, the aromatic residue Phe84, located within the dsRNA binding site [His39⁺–His60⁺–Phe84–His108⁺], alters the pKa of His60 through cation‐π interactions with its protonated state. This study offers new insights into the molecular mechanisms underlying pH‐dependent immune signaling via higher‐order assemblies and suggests potential applications for histidine in self‐assembling biomaterials.

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A Guide to the Continuous Constant pH Molecular Dynamics Methods in Amber and CHARMM [Article v1.0]

Cited by 23 publications

References 100 publications

GPU-Accelerated All-atom Particle-Mesh Ewald Continuous Constant pH Molecular Dynamics in Amber

GPU-Accelerated All-atom Particle-Mesh Ewald Continuous Constant pH Molecular Dynamics in Amber

GPU-Accelerated All-Atom Particle-Mesh Ewald Continuous Constant pH Molecular Dynamics in Amber

pH‐Dependent Assembly and Stability of Toll‐Like Receptor 3/dsRNA Signaling Complex: Insights from Constant pH Molecular Dynamics and Metadynamics Simulations

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