Simulations of Biomolecules in Electrolyte Solutions

2021

WIREs Comput Mol Sci

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Mutations that lead to drug resistance limit the efficacy of antibiotics, antiviral drugs, targeted cancer therapies, and other treatments. Accurately calculating protein-drug binding affinity changes upon mutations in the drug target is of high interest as this can yield a better understanding into how such mutations drive drug-resistance, especially when the mutation in question does not directly interfere with binding of the drug. The main aim of this article is to provide an up-to-date reference on the computational tools that are available for the calculation of Gibbs energy (free energy) changes upon mutation, their strengths, and limitations. The methods that are discussed include free energy calculations (free energy perturbation, thermodynamic integration, multistate Bennett acceptance ratio), analysis of molecular dynamics simulations (linear interaction energy, molecular mechanics [MM]/Poisson-Boltzmann solvated area, and MM/generalized Born solvated area), and methods that involve quantum mechanical calculations (including QM/MM). The possibility to use machine learning is also introduced. Given that the benefit of accurately calculating binding affinity changes upon mutation depends on comparing calculated values with experimental measurements, a brief survey on experimental methods and observables is provided. Examples of computational studies that go beyond calculating the Gibbs energy changes are given. Factors that need to be addressed by the computational chemist and potential pitfalls are discussed at length.

Section: Estimation Of the Gibbs Binding Energy Change Upon Mutation δδGb()s→r By Theoretical Methodsmentioning

confidence: 99%

Computational studies of protein–drug binding affinity changes upon mutations in the drug target

2021

WIREs Comput Mol Sci

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“…Less is known on the perturbation of water structure around solutes at the second shell and beyond, which is more difficult to study experimentally. Even simulations of ions in solutions are challenging, since there is a need to model correctly ion‐water, ion‐solute and ion‐ion interactions …”

Section: Figurementioning

confidence: 99%

“…Even simulations of ions in solutions are challenging, since there is a need to model correctly ion-water, ion-solute and ion-ion interactions. [16] To gain a better understanding of acetate-water interactions and how they depend on the cation, and on salt concentration, simulations of alkali acetate solutions were analysed in this study with respect to the acetate-water interactions and the structure of the water. Ideally, these should be studied at a wide range of concentrations, ranging from mM to several M. However, since reproduction of the structural and thermodynamic properties (activity coefficients) over such a range of concentrations is not always satisfactory with contemporary forcefields, [17] the solutions were studied only at concentrations of 0.1 M and 1 M which were deemed the most interesting from a biophysical point of view.…”

mentioning

confidence: 99%

Specific Ion and Concentration Effects in Acetate Solutions with Na⁺, K⁺ and Cs⁺

2019

ChemPhysChem

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How salt ions affect solutes and the water beyond the solvation shell is not well understood. Molecular dynamics simulations of alkali‐acetate solutions were analysed here in order to examine if, and how, different cations and solute concentrations affect the water structure and the interactions between water and acetates. The results revealed that water structure is perturbed to more than 1 nm away from the acetates and that this effect is more pronounced in physiological than in molar electrolyte concentrations. Analysis of simulations of a soluble protein revealed that the water orientation is perturbed to at least 1.5 nm from the protein structure. Furthermore, modifications to the orientation of water around carboxylate side chains were shown to depend on the local environment on the protein surface, and could extend to well over 1 nm, which may have an effect on protein dynamics during MD simulations in small water boxes.

“…For this reason, it is of utmost importance to estimate the hydration energy, which is referred to here as the Gibbs energy associated with the transfer of an ion from the gas phase to the aqueous milieu (of note, different terms are used in the literature, including “hydration energy”, “Gibbs’ hydration energy”, “hydration enthalpy” and “solvation energy”; these often but not always refer to exactly the same thermodynamic property). The binding of an ion to a protein, a nucleic acid, a lipid membrane, or any other biological interface necessitates the loss of the ion's hydration shell (at least partially) [10] . An 3+ ions are strongly hydrated, [20] with large (in absolute values) hydration energies and hence in analogy with Ln 3+ ions [21] do not bind just a random interface, even a polar one.…”

Section: Introductionmentioning

confidence: 99%

“…For example, colloids have a potential to be used for decontamination of radioactive waste. [3] Negatively charged biological interfaces[ 4 , 5 , 6 , 7 , 8 , 9 , 10 ] that bind cations with high enough affinity might be used in the same vein. The discovery that lanthanide (Ln) ions play a role in the biology of some microorganisms [11] and are used as cofactors in proteins [12] has further added to the interest in An‐protein interactions, since Ln and An share many similarities.…”

Section: Introductionmentioning

confidence: 99%

Estimating the Gibbs Hydration Energies of Actinium and Trans‐Plutonium Actinides

2022

ChemPhysChem

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The use of actinides for medical, scientific and technological purposes has gained momentum in the recent years. This creates a need to understand their interactions with biomolecules, both at the interface and as they become complexed. Calculation of the Gibbs binding energies of the ions to biomolecules, i. e., the Gibbs energy change associated with a transfer of an ion from the water phase to its binding site, could help to understand the actinides' toxicities and to design agents that bind them with high affinities. To this end, there is a need to obtain accurate reference values for actinide hydration, that for most actinides are not available from experiment. In this study, a set of ionic radii is developed that enables future calculations of binding energies for Pu 3 + and five actinides with renewed scientific and technological interest: Ac 3 + , Am 3 + , Cm 3 + , Bk 3 + and Cf 3 + . Reference hydration energies were calculated using quantum chemistry and ion solvation theory and agree well for all ions except Ac 3 + , where ion solvation theory seems to underestimate the magnitude of the Gibbs hydration energy. The set of radii and reference energies that are presented here provide means to calculate binding energies for actinides and biomolecules.