Large-Scale Study of Hydration Environments through Hydration Sites

Irwin, Benedict; Vukovic, Sinisa; Payne, Michael; Huggins, David J.

doi:10.1021/acs.jpcb.9b02490

Cited by 9 publications

(12 citation statements)

References 47 publications

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“…However, the double-decoupling method is computationally expensive, is difficult to set up, and involves the complex application of restraints or constraints. Other techniques, such as those based on inhomogeneous fluid solvation theory, can also predict the binding thermodynamics of water at the cost of additional simulations and calculations. − Due to these difficulties, FEP practitioners instead frequently experiment (often through trial and error) with including or excluding the “displaced” water molecule in the starting structure or use a fast algorithm to predict the occupancy of the hydration site prior to running FEP …”

Section: Introductionmentioning

confidence: 99%

Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo

Ross

Russell

Deng

et al. 2020

J. Chem. Theory Comput.

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The prediction of protein-ligand binding affinities using free energy perturbation (FEP) is becoming increasingly routine in structure-based drug discovery. Most FEP packages use molecular dynamics (MD) to sample the configurations of proteins and ligands, as MD is well-suited to capturing coupled motion. However, MD can be prohibitively inefficient at sampling water molecules that are buried within binding sites, which has severely limited the domain of applicability of FEP and its prospective usage in drug discovery. In this paper, we present an advancement of FEP that augments MD with grand canonical Monte Carlo (GCMC), an enhanced sampling method, to overcome the problem of sampling water. We accomplished this without degrading computational performance. On both old and newly assembled data sets of proteinligand complexes, we show that the use of GCMC in FEP is essential for accurate and robust predictions for ligand perturbations that disrupt buried water. File list (3) download file view on ChemRxiv enhancing_water_sampling.pdf (8.65 MiB) download file view on ChemRxiv supporting_info.pdf (0.90 MiB) download file view on ChemRxiv si_data.zip (33.28 MiB)

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Section: Introductionmentioning

confidence: 99%

Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo

Ross

Russell

Deng

et al. 2020

J. Chem. Theory Comput.

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show abstract

“…Other techniques, such as those based on inhomogenious fluid solvation theory, can also predict the binding thermodynamics of water at the cost of additional simulations and calculations. [7][8][9][10] Due to these difficulties, FEP practitioners instead often experiment (often through trial and error) with including or excluding the "displaced" water molecule in the starting structure, or use a fast algorithm to predict the occupancy of the hydration site prior to running FEP. 11 Recently, grand canonical Monte Carlo (GCMC) has shown great promise as a simulation framework to automatically incorporate the thermodynamics of buried water in ligand FEP calculations.…”

Section: Introductionmentioning

confidence: 99%

Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo

Ross¹,

Russell²,

Deng³

et al. 2020

Preprint

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<div>The prediction of protein-ligand binding affinities using free energy perturbation (FEP) is becoming increasingly routine in structure-based drug discovery. Most FEP packages use molecular dynamics (MD) to sample the configurations of proteins and ligands, as MD is well-suited to capturing coupled motion. However, MD can be prohibitively inefficient at sampling water molecules that are buried within binding sites, which has severely limited the domain of applicability of FEP and its prospective usage in drug discovery. In this paper, we present an advancement of FEP that augments MD with grand canonical Monte Carlo (GCMC), an enhanced sampling method, to overcome the problem of sampling water. We accomplished this without degrading computational performance. On both old and newly assembled data sets of proteinligand complexes, we show that the use of GCMC in FEP is essential for accurate and robust predictions for ligand perturbations that disrupt buried water. <br></div>

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“…68 Examining the free energy of water molecules on a per-residue basis over an ensemble shows the expected trend for the stability of water molecules, being greater adjacent to hydrophilic residues than for hydrophobic residues, as has been reported elsewhere. 47,52,58,60,63,70,77 Stability is further found to depend on the degree of burial of the water. Fewer water neighbors of a water molecule mostly means lower stability because of its diminished ability to form stabilizing HBs to the surrounding atoms in the more hydrophobic and asymmetric environment that biases orientations and lowers orientational entropy.…”

Section: Discussionmentioning

confidence: 90%

Total free energy analysis of fully hydrated proteins

et al. 2022

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The total free energy of a hydrated biomolecule and its corresponding decomposition of energy and entropy provides detailed information about regions of thermodynamic stability or instability. The free energies of four hydrated globular proteins with different net charges are calculated from a molecular dynamics simulation, with the energy coming from the system Hamiltonian and entropy using multiscale cell correlation. Water is found to be most stable around anionic residues, intermediate around cationic and polar residues, and least stable near hydrophobic residues, especially when more buried, with stability displaying moderate entropy-enthalpy compensation. Conversely, anionic residues in the proteins are energetically destabilized relative to singly solvated amino acids, while trends for other residues are less clear-cut. Almost all residues lose intraresidue entropy when in the protein, enthalpy changes are negative on average but may be positive or negative, and the resulting overall stability is moderate for some proteins and negligible for others. The free energy of water around single amino acids is found to closely match existing hydrophobicity scales. Regarding the effect of secondary structure, water is slightly more stable around loops, of intermediate stability around β strands and turns, and least stable around helices. An interesting asymmetry observed is that cationic residues stabilize a residue when bonded to its N-terminal side but destabilize it when on the Cterminal side, with a weaker reversed trend for anionic residues.

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Large-Scale Study of Hydration Environments through Hydration Sites

Cited by 9 publications

References 47 publications

Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo

Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo

Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo

Total free energy analysis of fully hydrated proteins

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