Predicting pKa Values with Continuous Constant pH Molecular Dynamics

Wallace, Jason A.; Shen, Jana

doi:10.1016/s0076-6879(09)66019-5

Cited by 88 publications

(124 citation statements)

References 88 publications

Supporting

Mentioning

117

Contrasting

Order By: Relevance

“…The CPHMD method has developed into an accurate and powerful tool for predicting protein pK a values 30 and for generating pH-dependent binding stability curves that can be directly compared with experiment. Ultimately, identifying the key pHsensitive residues using the CPHMD approach would allow us to design p19 proteins that have a higher affinity for siRNA which could be used to characterize RNA silencing complexes, to manage cellular levels of siRNA levels, and for discriminating between single-stranded RNA and dsRNA, and so forth.…”

Section: Discussionmentioning

confidence: 99%

“…Computational methods using molecular dynamics (MD) simulations an/or Monte Carlo (MC) sampling have been developed with considerable success for predicting protein pK a values (see reviews [28][29][30] ). Often referred to as constant pH MD (CPHMD) simulations, the titration coordinate is typically implemented in either a discrete manner [31][32][33][34][35][36][37][38][39][40][41][42][43] where protonation states are modified with an MC step at some regular MD interval or using a continuous function [44][45][46] that describes the protonation state via the k dynamics method developed by Brooks and coworkers.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

2013

View full text Add to dashboard Cite

: Tombusviruses, such as Carnation Italian ringspot virus (CIRV), encode a protein homodimer called p19 that is capable of suppressing RNA silencing in their infected hosts by binding to and sequestering short-interfering RNA (siRNA) away from the RNA silencing pathway. P19 binding stability has been shown to be sensitive to changes in pH but the specific amino acid residues involved have remained unclear. Using constant pH molecular dynamics simulations, we have identified key pH-dependent residues that affect CIRV p19-siRNA binding stability at various pH ranges based on calculated changes in the free energy contribution from each titratable residue. At high pH, the deprotonation of Lys60, Lys67, Lys71, and Cys134 has the largest effect on the binding stability. Similarly, deprotonation of several acidic residues (Asp9, Glu12, Asp20, Glu35, and/or Glu41) at low pH results in a decrease in binding stability. At neutral pH, residues Glu17 and His132 provide a small increase in the binding stability and we find that the optimal pH range for siRNA binding is between 7.0 and 10.0. Overall, our findings further inform recent experiments and are in excellent agreement with data on the pH-dependent binding profile.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

2013

View full text Add to dashboard Cite

show abstract

“…While it has been a standard practice to neutralize the simulation system in explicit-solvent simulations under periodic conditions with particle mesh Ewald (PME) treatment of extended electrostatics, 19 it has not been attempted in constant pH simulations. 20 This is because in such simulations the net charge of the solute may fluctuate as a result of exchanging proton(s) with solvent. Residual net charge is not a concern for methods that use GB implicit-solvent model for computing forces on λ particles (titration coordinates).…”

Section: Introductionmentioning

confidence: 99%

Charge-leveling and proper treatment of long-range electrostatics in all-atom molecular dynamics at constant pH

Wallace

Shen²

2012

The Journal of Chemical Physics

Self Cite

100

178

View full text Add to dashboard Cite

Recent development of constant pH molecular dynamics (CpHMD) methods has offered promise for adding pH-stat in molecular dynamics simulations. However, until now the working pH molecular dynamics (pHMD) implementations are dependent in part or whole on implicit-solvent models. Here we show that proper treatment of long-range electrostatics and maintaining charge neutrality of the system are critical for extending the continuous pHMD framework to the all-atom representation. The former is achieved here by adding forces to titration coordinates due to long-range electrostatics based on the generalized reaction field method, while the latter is made possible by a charge-leveling technique that couples proton titration with simultaneous ionization or neutralization of a co-ion in solution. We test the new method using the pH-replica-exchange CpHMD simulations of a series of aliphatic dicarboxylic acids with varying carbon chain length. The average absolute deviation from the experimental pK a values is merely 0.18 units. The results show that accounting for the forces due to extended electrostatics removes the large random noise in propagating titration coordinates, while maintaining charge neutrality of the system improves the accuracy in the calculated electrostatic interaction between ionizable sites. Thus, we believe that the way is paved for realizing pH-controlled all-atom molecular dynamics in the near future.

show abstract

“…6. Such graphics measure the degree of protonation, and are equivalent to the unprotonated fractions plots commonly reported in the literature (Wallace and Shen 2009). The data are for the turkey ovomucoid third domain (OMTKY3) at 10 mM.…”

Section: Titration Schemes Based On the Monte Carlo Methodsmentioning

confidence: 96%

“…Different aspects of available computational methods to study acid-base processes in biomolecules have been reviewed in the literature (Mongan and Case 2005;Chen et al 2008Chen et al , 2014Wallace and Shen 2009;Alexov et al 2011;Kim and McCammon 2016), evidencing their increasingly important role in biophysics, biochemistry, and biotechnological processes. Most of the reviews concentrated their discussions on atomistic level constant-pH (CpH) molecular dynamics (MD) techniques.…”

Section: Introductionmentioning

confidence: 99%

Development of constant-pH simulation methods in implicit solvent and applications in biomolecular systems

daSilva

Dias

2017

Biophys Rev

View full text Add to dashboard Cite

pH is a critical parameter for biological and technological systems directly related with electrical charges. It can give rise to peculiar electrostatic phenomena, which also makes them more challenging. Due to the quantum nature of the process, involving the forming and breaking of chemical bonds, quantum methods should ideally by employed. Nevertheless, due to the very large number of ionizable sites, different macromolecular conformations, salt conditions, and all other charged species, the CPU time cost simply becomes prohibitive for computer simulations, making this a quite complex problem. Simplified methods based on Monte Carlo sampling have been devised and will be reviewed here, highlighting the updated state-ofthe-art of this field, advantages, and limitations of different theoretical protocols for biomolecular systems (proteins and nucleic acids). Following a historical perspective, the discussion will be associated with the applications to protein interactions with other proteins, polyelectrolytes, and nanoparticles.

show abstract

Predicting pKa Values with Continuous Constant pH Molecular Dynamics

Cited by 88 publications

References 88 publications

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

Charge-leveling and proper treatment of long-range electrostatics in all-atom molecular dynamics at constant pH

Development of constant-pH simulation methods in implicit solvent and applications in biomolecular systems

Contact Info

Product

Resources

About