Assessment of Molecular Mechanics-based Zn2+ Models in Mono- and Bimetallic Ligand Binding Sites

Zn2+ ions play an important role in biology, but accurate sampling of metalloproteins using Molecular Mechanics remains challenging. Several models have been proposed to describe Zn2+ in biomolecular simulations, ranging from nonbonded models, employing classical 12-6 Lennard-Jones (LJ) potentials or extended LJ-potentials, to dummy-atom models and bonded models. We evaluated the performance of a large variety of these Zn2+ models in two challenging environments for which little is known about the performance of these methods, namely in a monometallic (Carbonic Anhydrase II) and a bimetallic ligand binding site (metallo-β-lactamase VIM-2). We focused on properties which are important for a stable, correct binding site description during molecular dynamics (MD) simulations, because a proper treatment of the metal coordination and forces are here essential. We observed that the strongest difference in performance of these Zn2+ models can be found in the description of interactions between Zn2+ and non-charged ligating atoms, such as the imidazole nitrogen in histidine residues. We further show that the nonbonded (12-6 LJ) models struggle most in the description of Zn2+-biomolecule interactions, while the inclusion of ion-induced dipole effects strongly improves the description between Zn2+ and non-charged ligating atoms. The octahedral dummy-atom models result in highly stable simulations and correct Zn2+ coordination, and are therefore highly suitable for binding sites containing an octahedral coordinated Zn2+ ion. The results from this evaluation study in ligand binding sites can guide structural studies of Zn2+ containing proteins, such as MD-refinement of docked ligand poses and long-term MD simulations.

Molecular dynamics simulation of the Pb(II) coordination in biological media via cationic dummy atom models

The coordination of Pb(II) in aqueous solutions containing thiols is a pivotal topic to the understanding of the pollutant potential of this cation. Based on its hard/soft borderline nature, Pb(II) forms stable hydrated ions as well as stable complexes with the thiol groups of proteins. In this paper, the modeling of Pb(II) coordination via classical molecular dynamics simulations was investigated to assess the possible use of non-bonded potentials for the description of the metal–ligand interaction. In particular, this study aimed at testing the capability of cationic dummy atom schemes—in which part of the mass and charge of the Pb(II) is fractioned in three or four sites anchored to the metal center—in reproducing the correct coordination geometry and, also, in describing the hard/soft borderline character of this cation. Preliminary DFT calculations were used to design two topological schemes, PB3 and PB4, that were subsequently implemented in the Amber force field and employed in molecular dynamics simulation of either pure water or thiol/thiolate-containing aqueous solutions. The PB3 scheme was then tested to model the binding of Pb(II) to the lead-sensing protein pbrR. The potential use of CDA topological schemes in the modeling of Pb(II) coordination was here critically discussed.

Dummy-atom modelling of stacked and helical nanostructures from solution scattering data

The availability of dummy-atom modelling programs to determine the shape of monodisperse globular particles from small-angle solution scattering data has led to outstanding scientific advances. However, there is no equivalent procedure that allows modelling of stacked, seemingly endless structures, such as helical systems. This work presents a bead-modelling algorithm that reconstructs the structural motif of helical and rod-like systems. The algorithm is based on a `projection scheme': by exploiting the recurrent nature of stacked systems, such as helices, the full structure is reduced to a single building-block motif. This building block is fitted by allowing random dummy-atom movements without an underlying grid. The proposed method is verified using a variety of analytical models, and examples are presented of successful shape reconstruction from experimental data sets. To make the algorithm available to the scientific community, it is implemented in a graphical computer program that encourages user interaction during the fitting process and also includes an option for shape reconstruction of globular particles.

Considerations on the model-free shape retrieval of inorganic nanocrystals from small-angle scattering data

Some new considerations on the model-free shape retrieval of inorganic nanocrystals based on the evaluation of averaged dummy atom models obtained from small-angle X-ray scattering data are presented. Scattering curves for shapes commonly found in inorganic nanocrystal systems were computed, from which dummy atom models were reconstructed usingDAMMINandDAMAVER. Cross sectional analysis methods were applied to allow a quantitative interpretation of these models, where special focus was directed towards the measurement of discrete model dimensions. By a quantitative comparison of the obtained models with the initial geometries, the limits of the proposed evaluation techniques were tested. Further, the proposed methods were utilized to study the influence of the accessible scattering vector as well as the effect of increasing size distributions on models retrieved byDAMMINandDAMAVER. The results confirm the usefulness of theseab initioshape-retrieval methods for slightly polydisperse systems. Finally, the practicability of the proposed techniques is demonstrated on an ensemble of chemically synthesized colloidal bismuth nanocrystals.

Incorporation of a hydration layer in the `dummy atom'ab initiostructural modelling of biological macromolecules

Ab initioalgorithms for the restoration of biomacromolecular structure from small-angle scattering data have gained popularity in the past 15 years. In particular, `dummy atom' models that require minimal information about the system under study have been proven capable of recovering the low-resolution shape of proteins and nucleic acids in many published works. However, consideration of solvated biological molecules as particles of uniform electron density contrast relative to the solvent neglects the presence of a hydration layer around their surface, leading to an overall apparent swelling of the obtained models and to a large overestimation of the volume of the particle. Here this problem is addressed by the introduction of an additional type of `dummy atom', representing the hydration layer. Successful applications of this new approach are illustrated for several proteins, and related results are compared with those from the programDAMMIN[Svergun (1999).Biophys. J.76, 2879–2886].