Applying efficient implicit nongeometric constraints in alchemical free energy simulations

Knight, Jennifer K.; Brooks, Charles L.

doi:10.1002/jcc.21921

Cited by 45 publications

(112 citation statements)

References 37 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…73 An identical setup was used successfully in our CPHMD MSλD model. As with the previous implementation of CPHMD for protein residues, 52-54 we have used the calibrated free energy of deprotonation (G bias ) as the fixed biasing potential value in our simulation.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Constant pH Molecular Dynamics Simulations of Nucleic Acids in Explicit Solvent

Goh

Knight

Brooks

2011

J. Chem. Theory Comput.

Self Cite

164

View full text Add to dashboard Cite

The nucleosides of adenine and cytosine have pKa values of 3.50 and 4.08, respectively, and are assumed to be unprotonated under physiological conditions. However, evidence from recent NMR and X-Ray crystallography studies has revealed the prevalence of protonated adenine and cytosine in RNA macromolecules. Such nucleotides with elevated pKa values may play a role in stabilizing RNA structure and participate in the mechanism of ribozyme catalysis. With the work presented here, we establish the framework and demonstrate the first constant pH MD simulations (CPHMD) for nucleic acids in explicit solvent in which the protonation state is coupled to the dynamical evolution of the RNA system via λ-dynamics. We adopt the new functional form λNexp for λ that was recently developed for Multi-Site λ-Dynamics (MSλD) and demonstrate good sampling characteristics in which rapid and frequent transitions between the protonated and unprotonated states at pH = pKa are achieved. Our calculated pKa values of simple nucleotides are in a good agreement with experimentally measured values, with a mean absolute error of 0.24 pKa units. This work demonstrates that CPHMD can be used as a powerful tool to investigate pH-dependent biological properties of RNA macromolecules.

show abstract

Section: Resultsmentioning

confidence: 99%

“…79 The simulation set up for λ dynamics is similar to that reported by Knight and Brooks. 72,73 The SHAKE algorithm 80 was used to constrain the hydrogen-heavy atom bond lengths. The Leapfrog Verlet integrator was used with an integration time step of 2 fs.…”

Section: Methodsmentioning

confidence: 99%

Constant pH Molecular Dynamics Simulations of Nucleic Acids in Explicit Solvent

Goh

Knight

Brooks

2011

J. Chem. Theory Comput.

Self Cite

164

View full text Add to dashboard Cite

show abstract

“…Constant pH molecular dynamics simulations (CPHMD) were performed using the CHARMM multi-site λ dynamics frame work (MSλD) 42,43 within the BLOCK facility. Details of this method, including the setup of each residue and its parameterization for the CHARMM 36 protein force-field, can be found elsewhere 32,44–46 .…”

Section: Methodsmentioning

confidence: 99%

Specific Binding of Cholesterol to C99 Domain of Amyloid Precursor Protein Depends Critically on Charge State of Protein

Panahi

Bandara

Pantelopulos

et al. 2016

J. Phys. Chem. Lett.

View full text Add to dashboard Cite

Recent NMR chemical shift measurements of the 99 residue C-terminal fragment of Amyloid Precursor Protein (APP-C99) in the presence of cholesterol provide evidence of binary complex formation between C99 and cholesterol in membrane mimetic environments. It has also been observed that the production of Aβ protein is enhanced under conditions of high cholesterol concentration. In this study, we investigated the impact of the charge state of C99 on the structure and stability of the C99-cholesterol complex. We observed that the binding of C99 to cholesterol depends critically on the charge state of Glu 693 (E22) and Asp 694 (D23). Evaluation of the pKa values of the Asp and Glu sidechains suggests that these residues may be predominantly neutral in existing experimental observations of a stable C99-cholesterol complex at lower pH (characteristic of the endosomal environment), while binding is destabilized near neutral pH (characteristic of the cytoplasm). These observations suggest that specific binding of cholesterol to C99 is a sensitive function of the pH encountered in vivo, with key E22 and D23 residues serving as a “pH switch” controlling C99-cholesterol binding.

show abstract

“…Multi-site λ-dynamics (MSλD), an alternative free energy method developed by Knight et. al , 19,20 allows for the simultaneous evaluation of the free energy differences between multiple compounds in a single simulation. However, MSλD has only been validated on alchemical calculations that are relatively simple, where the changes in fragments modeled do not significantly perturb the local environment.…”

Section: Introductionmentioning

confidence: 99%

Biasing Potential Replica Exchange Multisite λ-Dynamics for Efficient Free Energy Calculations

Armacost

Goh

Brooks

2015

J. Chem. Theory Comput.

Self Cite

View full text Add to dashboard Cite

Traditional free energy calculation methods are well known for their drawbacks in scalability and speed in converging results particularly for calculations with large perturbations. In the present work, we report on the development of biasing potential replica exchange multi-site λ-dynamics (BP-REX MSλD), which is a free energy method that is capable of performing simultaneous alchemical free energy transformations, including perturbations between flexible moieties. BP-REX MSλD and the original MSλD are applied to a series of symmetrical 2,5-benzoquinone derivatives covering a diverse chemical space and range of conformational flexibility. Improved λ-space sampling is observed for the BP-REX MSλD simulations, yielding a 2–5-fold increase in the number of transitions between substituents compared to traditional MSλD. We also demonstrate the efficacy of varying the value of c, the parameter that controls the ruggedness of the landscape mediating the sampling of λ-states, based on the flexibility of the fragment. Finally, we developed a protocol for maximizing the transition frequency between fragments. This protocol reduces the “kinetic barrier” for alchemically transforming fragments by grouping and ordering based on volume. These findings are applied to a challenging test set involving a series of geldanamycin-based inhibitors of heat shock protein 90 (Hsp90). Even though the perturbations span volume changes by as large as 60 Å3, the values for the free energy change achieve an average unsigned error (AUE) of 1.5 kcal/mol relative to experimental Kd measurements with a reasonable correlation (R = 0.56). Our results suggest that the BP-REX MSλD algorithm is a highly efficient and scalable free energy method, which when utilized will enable routine calculations on the order of hundreds of compounds using only a few simulations.

show abstract

Applying efficient implicit nongeometric constraints in alchemical free energy simulations

Cited by 45 publications

References 37 publications

Constant pH Molecular Dynamics Simulations of Nucleic Acids in Explicit Solvent

Constant pH Molecular Dynamics Simulations of Nucleic Acids in Explicit Solvent

Specific Binding of Cholesterol to C99 Domain of Amyloid Precursor Protein Depends Critically on Charge State of Protein

Biasing Potential Replica Exchange Multisite λ-Dynamics for Efficient Free Energy Calculations

Contact Info

Product

Resources

About