Sereina Riniker

Definition and testing of the GROMOS force-field versions 54A7 and 54B7.

New parameter sets of the GROMOS biomolecular force field, 54A7 and 54B7, are introduced. These parameter sets summarise some previously published force field modifications: The 53A6 helical propensities are corrected through new φ/ψ torsional angle terms and a modification of the N–H, C=O repulsion, a new atom type for a charged −CH3 in the choline moiety is added, the Na+ and Cl− ions are modified to reproduce the free energy of hydration, and additional improper torsional angle types for free energy calculations involving a chirality change are introduced. The new helical propensity modification is tested using the benchmark proteins hen egg-white lysozyme, fox1 RNA binding domain, chorismate mutase and the GCN4-p1 peptide. The stability of the proteins is improved in comparison with the 53A6 force field, and good agreement with a range of primary experimental data is obtained.

On developing coarse-grained models for biomolecular simulation: a review

So-called coarse-grained models are a popular type of model for accessing long time scales in simulations of biomolecular processes. Such models are coarse-grained with respect to atomic models. But any modelling of processes or substances involves coarse-graining, i.e. the elimination of non-essential degrees of freedom and interactions from a more fine-grained level of modelling. The basic ingredients of developing coarse-grained models based on the properties of fine-grained models are reviewed, together with the conditions that must be satisfied in order to preserve the correct physical mechanisms in the coarse-graining process. This overview should help the reader to determine how realistic a coarse-grained model of a biomolecular system is, i.e. whether it reflects the underlying physical mechanisms or merely provides a set of pretty pictures of the process or substances of interest.

A simple, efficient polarizable coarse-grained water model for molecular dynamics simulations

The development of coarse-grained (CG) models that correctly represent the important features of compounds is essential to overcome the limitations in time scale and system size currently encountered in atomistic molecular dynamics simulations. Most approaches reported in the literature model one or several molecules into a single uncharged CG bead. For water, this implicit treatment of the electrostatic interactions, however, fails to mimic important properties, e.g., the dielectric screening. Therefore, a coarse-grained model for water is proposed which treats the electrostatic interactions between clusters of water molecules explicitly. Five water molecules are embedded in a spherical CG bead consisting of two oppositely charged particles which represent a dipole. The bond connecting the two particles in a bead is unconstrained, which makes the model polarizable. Experimental and all-atom simulated data of liquid water at room temperature are used for parametrization of the model. The experimental density and the relative static dielectric permittivity were chosen as primary target properties. The model properties are compared with those obtained from experiment, from clusters of simple-point-charge water molecules of appropriate size in the liquid phase, and for other CG water models if available. The comparison shows that not all atomistic properties can be reproduced by a CG model, so properties of key importance have to be selected when coarse graining is applied. Yet, the CG model reproduces the key characteristics of liquid water while being computationally 1-2 orders of magnitude more efficient than standard fine-grained atomistic water models.

New functionalities in the GROMOS biomolecular simulation software

Since the most recent description of the functionalities of the GROMOS software for biomolecular simulation in 2005 many new functions have been implemented. In this article, the new functionalities that involve modified forces in a molecular dynamics (MD) simulation are described: the treatment of electronic polarizability, an implicit surface area and internal volume solvation term to calculate interatomic forces, functions for the GROMOS coarse‐grained supramolecular force field, a multiplicative switching function for nonbonded interactions, adiabatic decoupling of a number of degrees of freedom with temperature or force scaling to enhance sampling, and nonequilibrium MD to calculate the dielectric permittivity or viscosity. Examples that illustrate the use of these functionalities are given.

Open-source platform to benchmark fingerprints for ligand-based virtual screening

Similarity-search methods using molecular fingerprints are an important tool for ligand-based virtual screening. A huge variety of fingerprints exist and their performance, usually assessed in retrospective benchmarking studies using data sets with known actives and known or assumed inactives, depends largely on the validation data sets used and the similarity measure used. Comparing new methods to existing ones in any systematic way is rather difficult due to the lack of standard data sets and evaluation procedures. Here, we present a standard platform for the benchmarking of 2D fingerprints. The open-source platform contains all source code, structural data for the actives and inactives used (drawn from three publicly available collections of data sets), and lists of randomly selected query molecules to be used for statistically valid comparisons of methods. This allows the exact reproduction and comparison of results for future studies. The results for 12 standard fingerprints together with two simple baseline fingerprints assessed by seven evaluation methods are shown together with the correlations between methods. High correlations were found between the 12 fingerprints and a careful statistical analysis showed that only the two baseline fingerprints were different from the others in a statistically significant way. High correlations were also found between six of the seven evaluation methods, indicating that despite their seeming differences, many of these methods are similar to each other.

The impact of molecular dynamics on drug design: applications for the characterization of ligand–macromolecule complexes

Among all tools available to design new drugs, molecular dynamics (MD) simulations have become an essential technique. Initially developed to investigate molecular models with a limited number of atoms, computers now enable investigations of large macromolecular systems with a simulation time reaching the microsecond range. The reviewed articles cover four years of research to give an overview on the actual impact of MD on the current medicinal chemistry landscape with a particular emphasis on studies of ligand-protein interactions. With a special focus on studies combining computational approaches with data gained from other techniques, this review shows how deeply embedded MD simulations are in drug design strategies and articulates what the future of this technique could be.

Calculation of Relative Free Energies for Ligand-Protein Binding, Solvation, and Conformational Transitions Using the GROMOS Software

The calculation of the relative free energies of ligand-protein binding, of solvation for different compounds, and of different conformational states of a polypeptide is of considerable interest in the design or selection of potential enzyme inhibitors. Since such processes in aqueous solution generally comprise energetic and entropic contributions from many molecular configurations, adequate sampling of the relevant parts of configurational space is required and can be achieved through molecular dynamics simulations. Various techniques to obtain converged ensemble averages and their implementation in the GROMOS software for biomolecular simulation are discussed, and examples of their application to biomolecules in aqueous solution are given.

Multi-Resolution Simulation of Biomolecular Systems: A Review of Methodological Issues

Theoretical-computational modeling with an eye to explaining experimental observations in regard to a particular chemical phenomenon or process requires choices concerning essential degrees of freedom and types of interactions and the generation of a Boltzmann ensemble or trajectories of configurations. Depending on the degrees of freedom that are essential to the process of interest, for example, electronic or nuclear versus atomic, molecular or supra-molecular, quantum- or classical-mechanical equations of motion are to be used. In multi-resolution simulation, various levels of resolution, for example, electronic, atomic, supra-atomic or supra-molecular, are combined in one model. This allows an enhancement of the computational efficiency, while maintaining sufficient detail with respect to particular degrees of freedom. The basic challenges and choices with respect to multi-resolution modeling are reviewed and as an illustration the differential catalytic properties of two enzymes with similar folds but different substrates with respect to these substrates are explored using multi-resolution simulation at the electronic, atomic and supra-molecular levels of resolution.

Solvating atomic level fine-grained proteins in supra-molecular level coarse-grained water for molecular dynamics simulations

Simulation of the dynamics of a protein in aqueous solution using an atomic model for both the protein and the many water molecules is still computationally extremely demanding considering the time scale of protein motions. The use of supra-atomic or supra-molecular coarse-grained (CG) models may enhance the computational efficiency, but inevitably at the cost of reduced accuracy. Coarse-graining solvent degrees of freedom is likely to yield a favourable balance between reduced accuracy and enhanced computational speed. Here, the use of a supra-molecular coarse-grained water model that largely preserves the thermodynamic and dielectric properties of atomic level fine-grained (FG) water in molecular dynamics simulations of an atomic model for four proteins is investigated. The results of using an FG, a CG, an implicit, or a vacuum solvent environment of the four proteins are compared, and for hen egg-white lysozyme a comparison to NMR data is made. The mixed-grained simulations do not show large differences compared to the FG atomic level simulations, apart from an increased tendency to form hydrogen bonds between long side chains, which is due to the reduced ability of the supra-molecular CG beads that represent five FG water molecules to make solvent-protein hydrogen bonds. But, the mixed-grained simulations are at least an order of magnitude faster than the atomic level ones.

Structural Effects of an Atomic-Level Layer of Water Molecules around Proteins Solvated in Supra-Molecular Coarse-Grained Water

Atomistic molecular dynamics simulations of proteins in aqueous solution are still limited to the multinanosecond time scale and multinanometer range by computational cost. Combining atomic solutes with a supra-molecular solvent model in hybrid fine-grained/coarse-grained (FG/CG) simulations allows atomic detail in the region of interest while being computationally more efficient. A recent comparison of the properties of four proteins in CG water versus FG water showed the preservation of the secondary and tertiary structure with a computational speed-up of at least an order of magnitude. However, an increased occurrence of hydrogen bonds between side chains was observed due to a lack of hydrogen-bonding partners in the supra-molecular solvent. Here, the introduction of a FG water layer around the protein to recover the hydrogen-bonding pattern of the atomistic simulations is studied. Three layer thicknesses of 0.2, 0.4, and 0.8 nm are considered. A layer thickness of 0.8 nm is found sufficient to recover the behavior of the proteins in the atomistic simulations, whereas the hybrid simulation is still three times more efficient than the atomistic one and the cutoff radius for nonbonded interactions could be increased from 1.4 to 2.0 nm.