Simulated scaling method for localized enhanced sampling and simultaneous “alchemical” free energy simulations: A general method for molecular mechanical, quantum mechanical, and quantum mechanical/molecular mechanical simulations

Zhang, Lipeng; Fajer, Mikolai; Yang, Wei

doi:10.1063/1.2424700

Cited by 89 publications

(112 citation statements)

References 56 publications

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“…Tempering is a technique (12,(41)(42)(43)(44)(45)(46)(47)(48) that accelerates sampling by occasionally raising and lowering the temperature. In this study, we adopted a single-trajectory-based tempering method reported previously (12) for computing efficiency.…”

Section: Methodsmentioning

confidence: 99%

Folding helical proteins in explicit solvent using dihedral-biased tempering

Zhang

2012

Proc. Natl. Acad. Sci. U.S.A.

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Using a single-trajectory-based tempering method with a high-temperature dihedral bias, we repeatedly folded four helical proteins [ α 3 D (PDB ID: 2A3D, 73 residues), α 3 W (1LQ7, 67 residues), Fap1-NR α (2KUB, 81 residues) and S-836 (2JUA, 102 residues)] and some of the mutants in explicit solvent within several microseconds. The lowest root-mean-square deviations of backbone atoms from the experimentally determined structures were 1.9, 1.4, 1.0, and 2.1 Å, respectively. Cluster analyses of folding trajectories showed the native conformation usually occupied the most populated cluster. The simulation protocol can be applied to large-scale simulations of other helical proteins on commonly accessible computing platforms.

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Section: Methodsmentioning

confidence: 99%

Folding helical proteins in explicit solvent using dihedral-biased tempering

Zhang

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…With the MRWQ scheme, one might expect even better sampling since walking between λ windows might induce "conformational tunneling" effect [67]. However, we observe that MRWQ simulations lead to too low a pK a shift by more than 1 pK a unit.…”

Section: Pk a Calculations For Buried Residuesmentioning

confidence: 90%

Toward molecular models of proton pumping: Challenges, methods and relevant applications

et al. 2011

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Motivated by several long-lasting mechanistic questions for biomolecular proton pumps, we have engaged in developing hybrid quantum mechanical/molecular mechanical (QM/MM) methods that allow an efficient and reliable description of long-range proton transport in transmembrane proteins. In this review, we briefly discuss several relevant issues: the need to develop a "multi-scale" generalized solvent boundary potential (GSBP) for the analysis of chemical events in large trans-membrane proteins, approaches to validate such a protocol, and the importance of improving the flexibility of QM/MM Hamiltonian. Several recent studies of model and realistic protein systems are also discussed to help put the discussions into context. Collectively, these studies suggest that the QM/MM-GSBP framework based on an approximate density functional theory (SCC-DFTB) as QM holds the promise to strike the proper balance between computational efficiency, accuracy and generality. With additional improvements in the methodology and recent developments by others, especially powerful sampling techniques, this "multi-scale" framework will be able to help unlock the secrets of proton pumps and other biomolecular machines.proton pumping, QM/MM simulations, SCC-DFTB, microscopic pK a , multi-scale simulations

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“…The need of employing enhanced sampling techniques in the free energy simulations, [39,40] on the other hand, seems much more compelling and can potentially make a very large impact on the computed pK a values. Multiple nanoseconds of simulations per λ window in the most straightforward thermodynamic integration framework, as done here, are sufficient only if the structural response is very local in nature and the involvement of multiple hydration states [11] is not severe.…”

Section: Discussionmentioning

confidence: 99%

pK_a of Residue 66 in Staphylococal nuclease. I. Insights from QM/MM Simulations with Conventional Sampling

Ghosh

Cui

2008

J. Phys. Chem. B

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A combined quantum mechanical/molecular mechanical (QM/MM) potential function is used in a thermodynamic integration approach to calculate the pK a of residue 66 in two mutants (V66E, V66D) of Staphylococal nuclease relative to solution. Despite the similarity in chemical nature and experimentally measured pK a of the two buried titritable residues, the behaviors of the two mutants and the computed pK a values vary greatly in the simulations. For Glu66, the sidechain is consistently observed to spontaneously flip out from the protein interior during titration, and the overall protein structure remains stable throughout the simulations. The computed pK a shifts using conventional sampling techniques with multiple nanoseconds per λ window (Set A & B) are generally close to the experimental value, therefore indicating that large-scale conformational rearrangements are not as important for V66E as suggested by the recent study of Warshel and co-worker. For Asp66, by contrast, flipping of the shorter sidechain is not sufficient for getting adequate solvent stabilization of the ionized state. As a result, more complex behaviors such as partial unfolding of a nearby β-sheet region is observed, and the computed pK a shift is substantially higher than the experimental value unless Asp66 is biased to adopt the similar configurations as Glu66 in the V66E simulations. Collectively, these studies suggest that the lack of electronic polarization is not expected to be the dominant source of error in microscopic pK a shift calculations, while the need of enhanced sampling is more compelling for predicting the pK a of buried residues. Furthermore, the comparison between V66E and V66D also highlights that the microscopic interpretation of similar apparent pK a values and effective "dielectric constants" of proteins can vary greatly in terms of the residues that make key contributions and the scale of structural/hydration response to titration, the latter of which is difficult to predict a priori. Perturbative analyses of interactions that contribute to the titration free energy point to mutants that can be used to verify the microscopic mechanisms of titration in V66E/ D SNase proteins.

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Simulated scaling method for localized enhanced sampling and simultaneous “alchemical” free energy simulations: A general method for molecular mechanical, quantum mechanical, and quantum mechanical/molecular mechanical simulations

Cited by 89 publications

References 56 publications

Folding helical proteins in explicit solvent using dihedral-biased tempering

Folding helical proteins in explicit solvent using dihedral-biased tempering

Toward molecular models of proton pumping: Challenges, methods and relevant applications

pK_a of Residue 66 in Staphylococal nuclease. I. Insights from QM/MM Simulations with Conventional Sampling

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Simulated scaling method for localized enhanced sampling and simultaneous “alchemical” free energy simulations: A general method for molecular mechanical, quantum mechanical, and quantum mechanical/molecular mechanical simulations

Cited by 89 publications

References 56 publications

Folding helical proteins in explicit solvent using dihedral-biased tempering

Folding helical proteins in explicit solvent using dihedral-biased tempering

Toward molecular models of proton pumping: Challenges, methods and relevant applications

pKa of Residue 66 in Staphylococal nuclease. I. Insights from QM/MM Simulations with Conventional Sampling

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pK_a of Residue 66 in Staphylococal nuclease. I. Insights from QM/MM Simulations with Conventional Sampling