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We present an unsupervised data processing workflow that is specifically designed to obtain a fast conformational clustering of long molecular dynamics simulation trajectories. In this approach, we combine two dimensionality reduction algorithms (cc_analysis and encodermap) with a density-based spatial clustering algorithm (hierarchical density-based spatial clustering of applications with noise). The proposed scheme benefits from the strengths of the three algorithms while avoiding most of the drawbacks of the individual methods. Here, the cc_analysis algorithm is applied for the first time to molecular simulation data. The encodermap algorithm complements cc_analysis by providing an efficient way to process and assign large amounts of data to clusters. The main goal of the procedure is to maximize the number of assigned frames of a given trajectory while keeping a clear conformational identity of the clusters that are found. In practice, we achieve this by using an iterative clustering approach and a tunable root-mean-square-deviation-based criterion in the final cluster assignment. This allows us to find clusters of different densities and different degrees of structural identity. With the help of four protein systems, we illustrate the capability and performance of this clustering workflow: wild-type and thermostable mutant of the Trp-cage protein (TC5b and TC10b), NTL9, and Protein B. Each of these test systems poses their individual challenges to the scheme, which, in total, give a nice overview of the advantages and potential difficulties that can arise when using the proposed method.

The abundance of plasma membrane-resident receptors and transporters has to be tightly regulated by ubiquitin-mediated endosomal degradation for the proper coordination of environmental stimuli and intracellular signaling. Arabidopsis OVARIAN TUMOR PROTEASE (OTU) 11 and OTU12 are plasma membrane-localized deubiquitylating enzymes (DUBs) that bind to phospholipids through a polybasic motif in the OTU domain. Here we show that the DUB activity of OTU11 and OTU12 towards K63-linked ubiquitin is stimulated by binding to lipid membranes containing anionic lipids. In addition, we show that the DUB activity of OTU11 against K6- and K11-linkages is also stimulated by anionic lipids, and that OTU11 and OTU12 can modulate the endosomal degradation of a model cargo and the auxin efflux transporter PIN2-GFP in vivo. Our results suggest that the catalytic activity of OTU11 and OTU12 is tightly connected to their ability to bind membranes and that OTU11 and OTU12 are involved in the fine-tuning of plasma membrane proteins in Arabidopsis.

Covalent attachment of ubiquitin (Ub) to proteins is a highly versatile posttranslational modification. Moreover, Ub is not only a modifier but itself is modified by phosphorylation and lysine acetylation. However, the functional consequences of Ub acetylation are poorly understood. By generation and comprehensive characterization of all seven possible mono-acetylated Ub variants, we show that each acetylation site has a particular impact on Ub structure. This is reflected in selective usage of the acetylated variants by different E3 ligases and overlapping but distinct interactomes, linking different acetylated variants to different cellular pathways. Notably, not only electrostatic but also steric effects contribute to acetylation-induced changes in Ub structure and, thus, function. Finally, we provide evidence that p300 acts as a position-specific Ub acetyltransferase and HDAC6 as a general Ub deacetylase. Our findings provide intimate insights into the structural and functional consequences of Ub acetylation and highlight the general importance of Ub acetylation.

One ongoing topic of research in MD simulations is how to enable sampling to chemically and biologically relevant time scales. We address this question by introducing a back-mapping based sampling (BMBS) that combines multiple aspects of different sampling techniques. BMBS uses coarse grained (CG) free energy surfaces (FESs) and dimensionality reduction to initiate new atomistic simulations. These new simulations are started from atomistic conformations that were back-mapped from CG points all over the FES in order to sample the entire accessible phase space as fast as possible. In the context of BMBS, we address relevant back-mapping related questions like where to start the back-mapping from and how to judge the atomistic ensemble that results from the BMBS. The latter is done with the use of the earth mover’s distance, which allows us to quantitatively compare distributions of CG and atomistic ensembles. By using this metric, we can also show that the BMBS is able to correct inaccuracies of the CG model. In this paper, BMBS is applied to a just recently introduced neural network (NN) based approach for a radical coarse graining to predict free energy surfaces for oligopeptides. The BMBS scheme back-maps these FESs to the atomistic scale, justifying and complementing the proposed NN based CG approach. The efficiency benefit of the algorithm scales with the length of the oligomer. Already for the heptamers, the algorithm is about one order of magnitude faster in sampling compared to a standard MD simulation. published

We show here that molecular resolution is inherently hybrid in terms of relative separation: If molecules are close to each other, they must be characterized by a fine-grained (geometrically detailed) model, yet if molecules are far from each other, they may be described by a coarse-grained (isotropically simplified) model. We notably present an analytical expression for relating the two models by energy conservation. This hybrid framework is correspondingly capable of retrieving the structural and thermal behavior of various multi-component and multi-phase fluids across state space.

Hsp70 chaperones assist de novo folding of newly synthesized proteins in all cells. In yeast, the specialized Hsp70 Ssb directly binds to ribosomes. The structural basis and functional mode of recruitment of Ssb to ribosomes is not understood. Here, we present the molecular details underlying ribosome binding of Ssb in Saccharomyces cerevisiae. This interaction is multifaceted, involving the co-chaperone RAC and two specific regions within Ssb characterized by positive charges. The C-terminus of Ssb mediates the key contact and a second attachment point is provided by a KRR-motif in the substrate binding domain. Strikingly, ribosome binding of Ssb is not essential. Autonomous ribosome attachment becomes necessary if RAC is absent, suggesting a dual mode of Ssb recruitment to nascent chains. We propose, that the multilayered ribosomal interaction allows positioning of Ssb in an optimal orientation to the tunnel exit guaranteeing an efficient nascent polypeptide interaction., The correct folding of proteins often requires the intervention molecular chaperones, which can occur co-translationally. Here the authors identify elements of yeast Ssb (Hsp70) that mediate ribosomal binding, and suggest a mechanism that directs efficient interaction of Ssb with the nascent chain.

This special topics issue offers a broad perspective on recent theoretical and computational soft matter science, providing state of the art advances in many of its sub-fields. As is befitting for a discipline as diverse as soft matter, the papers collected here span a considerable range of subjects and questions, but they also illustrate numerous connections into both fundamental science and technological/industrial applications, which have accompanied the field since its earliest days. This issue is dedicated to Kurt Kremer, on the occasion of his 60th birthday, honouring his role in establishing this exciting field and consolidating its standing in the frame of current science and technology.

We use coarse-grained (CG) simulations to study the deformation of empty Cowpea Chlorotic Mottle Virus (CCMV) capsids under uniaxial compression, from the initial elastic response up to capsid breakage. Our CG model is based on the MARTINI force field and has been amended by a stabilizing elastic network, acting only within individual proteins, that was tuned to capture the fluctuation spectrum of capsid protein dimers, obtained from all atom simulations. We have previously shown that this model predicts force-compression curves that match AFM indentation experiments on empty CCMV capsids. Here we investigate details of the actual breaking events when the CCMV capsid finally fails. We present a symmetry classification of all relevant protein contacts and show that they differ significantly in terms of stability. Specifically, we show that interfaces which break readily are precisely those which are believed to form last during assembly, even though some of them might share the same contacts as other non-breaking interfaces. In particular, the interfaces that form pentamers of dimers never break, while the virtually identical interfaces within hexamers of dimers readily do. Since these units differ in the large-scale geometry and, most noticeably, the cone-angle at the center of the 5- or 6-fold vertex, we propose that the hexameric unit fails because it is pre-stressed. This not only suggests that hexamers of dimers form less frequently during the early stages of assembly; it also offers a natural explanation for the well-known β-barrel motif at the hexameric center as a post-aggregation stabilization mechanism. Finally, we identify those amino acid contacts within all key protein interfaces that are most persistent during compressive deformation of the capsid, thereby providing potential targets for mutation studies aiming to elucidate the key contacts upon which overall stability rests. published

FAT10 is a ubiquitin-like modifier that directly targets proteins for proteasomal degradation. Here, we report the high-resolution structures of the two individual ubiquitin-like domains (UBD) of FAT10 that are joined by a flexible linker. While the UBDs of FAT10 show the typical ubiquitin-fold, their surfaces are entirely different from each other and from ubiquitin explaining their unique binding specificities. Deletion of the linker abrogates FAT10-conjugation while its mutation blocks auto-FAT10ylation of the FAT10-conjugating enzyme USE1 but not bulk conjugate formation. FAT10- but not ubiquitin-mediated degradation is independent of the segregase VCP/p97 in the presence but not the absence of FAT10’s unstructured N-terminal heptapeptide. Stabilization of the FAT10 UBDs strongly decelerates degradation suggesting that the intrinsic instability of FAT10 together with its disordered N-terminus enables the rapid, joint degradation of FAT10 and its substrates without the need for FAT10 de-conjugation and partial substrate unfolding., The ubiquitin-like modifier FAT10 is composed of two ubiquitin-like domains (UBDs). Here the authors present the FAT10 UBD structures and show that the unstructured FAT10 N-terminal heptapeptide together with the poor stability of FAT10 facilitate the rapid proteasomal targeting of FAT10 along with its substrates.

FAT10 is a ubiquitin-like modifier that directly targets proteins for proteasomal degradation. Here, we report the high-resolution structures of the two individual ubiquitin-like domains (UBD) of FAT10 that are joined by a flexible linker. While the UBDs of FAT10 show the typical ubiquitin-fold, their surfaces are entirely different from each other and from ubiquitin explaining their unique binding specificities. Deletion of the linker abrogates FAT10-conjugation while its mutation blocks auto-FAT10ylation of the FAT10-conjugating enzyme USE1 but not bulk conjugate formation. FAT10- but not ubiquitin-mediated degradation is independent of the segregase VCP/p97 in the presence but not the absence of FAT10’s unstructured N-terminal heptapeptide. Stabilization of the FAT10 UBDs strongly decelerates degradation suggesting that the intrinsic instability of FAT10 together with its disordered N-terminus enables the rapid, joint degradation of FAT10 and its substrates without the need for FAT10 de-conjugation and partial substrate unfolding.

In the last few decades, computer simulations have become a fundamental tool in the field of soft matter science, allowing researchers to investigate the properties of a large variety of systems. Nonetheless, even the most powerful computational resources presently available are, in general, sufficient to simulate complex biomolecules only for a few nanoseconds. This limitation is often circumvented by using coarse-grained models, in which only a subset of the system’s degrees of freedom is retained; for an effective and insightful use of these simplified models; however, an appropriate parametrization of the interactions is of fundamental importance. Additionally, in many cases the removal of fine-grained details in a specific, small region of the system would destroy relevant features; such cases can be treated using dual-resolution simulation methods, where a subregion of the system is described with high resolution, and a coarse-grained representation is employed in the rest of the simulation domain. In this review we discuss the basic notions of coarse-graining theory, presenting the most common methodologies employed to build low-resolution descriptions of a system and putting particular emphasis on their similarities and differences. The AdResS and H-AdResS adaptive resolution simulation schemes are reported as examples of dual-resolution approaches, especially focusing in particular on their theoretical background.

Coarse grained (CG) models are widely used in studying peptide self-assembly and nanostructure formation. One of the recurrent challenges in CG modeling is the problem of limited transferability, for example to different thermodynamic state points and system compositions. Understanding transferability is generally a prerequisite to knowing for which problems a model can be reliably used and predictive. For peptides, one crucial transferability question is whether a model reproduces the molecule's conformational response to a change in its molecular environment. This is of particular importance since CG peptide models often have to resort to auxiliary interactions that aid secondary structure formation. Such interactions take care of properties of the real system that are per se lost in the coarse graining process such as dihedral-angle correlations along the backbone or backbone hydrogen bonding. These auxiliary interactions may then easily overstabilize certain conformational propensities and therefore destroy the ability of the model to respond to stimuli and environment changes, i.e. they impede transferability. In the present paper we have investigated a short peptide with amphiphilic EALA repeats which undergoes conformational transitions between a disordered and a helical state upon a change in pH value or due to the presence of a soft apolar/polar interface. We designed a base CG peptide model that does not carry a specific (backbone) bias towards a secondary structure. This base model was combined with two typical approaches of ensuring secondary structure formation, namely a C α -C α -C α -C α pseudodihedral angle potential or a virtual site interaction that mimics hydrogen bonding. We have investigated the ability of the two resulting CG models to represent the environment-induced conformational changes in the helix-coil equilibrium of EALA. We show that with both approaches a CG peptide model can be obtained that is environment-transferable and that correctly represents the peptide's conformational response to different stimuli compared to atomistic reference simulations. The two types of auxiliary interactions lead to different kinetic behavior as well as to different structural properties for fully formed helices and folding intermediates, and we discuss the advantages and disadvantages of these approaches.

Hybrid simulations, in which part of the system is represented at atomic resolution and the remaining part at a reduced, coarse-grained, level offer a powerful way to combine the accuracy associated with the atomistic force fields to the sampling speed obtained with coarse-grained (CG) potentials. In this work we introduce a straightforward scheme to perform hybrid simulations, making use of virtual sites to couple the two levels of resolution. With the help of these virtual sites interactions between molecules at different levels of resolution, i.e. between CG and atomistic molecules, are treated the same way as the pure CG–CG interactions. To test our method, we combine the Gromos atomistic force field with a number of coarse-grained potentials, obtained through several approaches that are designed to obtain CG potentials based on an existing atomistic model, namely iterative Boltzmann inversion, force matching, and a potential of mean force subtraction procedure (SB). We also explore the use of the MARTINI force field for the CG potential. A simple system, consisting of atomistic butane molecules dissolved in CG butane, is used to study the performance of our hybrid scheme. Based on the potentials of mean force for atomistic butane in CG solvent, and the properties of 1 : 1 mixtures of atomistic and CG butane which should exhibit ideal mixing behavior, we conclude that the MARTINI and SB potentials are particularly suited to be combined with the atomistic force field. The MARTINI potential is subsequently used to perform hybrid simulations of atomistic dialanine peptides in both CG butane and water. Compared to a fully atomistic description of the system, the hybrid description gives similar results provided that the dielectric screening of water is accounted for. Within the field of biomolecules, our method appears ideally suited to study e.g.protein-ligand binding, where the active site and ligand are modeled in atomistic detail and the rest of the protein, together with the solvent, is coarse-grained. published

The correct interplay of interactions between protein, pigment and lipid molecules is highly relevant for our understanding of the association behavior of the light harvesting complex (LHCII) of green plants. To cover the relevant time and length scales in this multicomponent system, a multi-scale simulation ansatz is employed that subsequently uses a classical all atomistic (AA) model to derive a suitable coarse grained (CG) model which can be backmapped into the AA resolution, aiming for a seamless conversion between two scales. Such an approach requires a faithful description of not only the protein and lipid components, but also the interaction functions for the indispensable pigment molecules, chlorophyll b and chlorophyll a (referred to as chl b/chl a). In this paper we develop a CG model for chl b and chl a in a dipalmitoylphosphatidyl choline (DPPC) bilayer system. The structural properties and the distribution behavior of chl within the lipid bilayer in the CG simulations are consistent with those of AA reference simulations. The non-bonded potentials are parameterized such that they fit to the thermodynamics based MARTINI force-field for the lipid bilayer and the protein. The CG simulation shows chl aggregation in the lipid bilayer which is supported by fluorescence quenching experiments. It is shown that the derived chl model is well suited for CG simulations of stable, structurally consistent, trimeric LHCII and can in the future be used to study their large scale aggregation behavior. published

An iterative algorithm based on fast Fourier transforms is proposed to solve the Poisson equation for systems of heterogeneous permittivity (e.g., solute cavity in a solvent) under periodic boundary conditions. The method makes explicit use of the dipole–dipole interaction tensor, and is thus easily generalizable to arbitrary forms of electrostatic interactions (e.g., Coulomb’s law with straight or smooth cutoff truncation). The convergence properties of the algorithm and the influence of various model parameters are investigated in detail, and a set of appropriate values for these parameters is determined. The algorithm is further tested by application to three types of systems (a single spherical ion, two spherical ions, and small biomolecules), and comparison with analytical results (single ion) and with results obtained using a finite-difference solver under periodic boundary conditions. The proposed algorithm performs very well in terms of accuracy and convergence properties, with an overall speed comparable in the current implementation to that of a typical finite-difference solver. Future developments and applications of the algorithm will include: (i) the assessment of periodicity- and cutoff-induced artifacts in explicit-solvent simulations; (ii) the design of new electrostatic schemes for explicit-solvent simulations mimicking more accurately bulk solution; (iii) a faster evaluation of solvation free energies based on continuum electrostatics in cases where periodicity-induced artifacts can be neglected. published

Understanding the connections between the characteristic dynamical time scales associated with a coarse-grained (CG) and a detailed representation is central to the applicability of the coarse-graining methods to understand molecular processes. The process of coarse graining leads to an accelerated dynamics, owing to the smoothening of the underlying free-energy landscapes. Often a single time-mapping factor is used to relate the time scales associated with the two representations. We critically examine this idea using a model system ideally suited for this purpose. Single molecular transport properties are studied via molecular dynamics simulations of the CG and atomistic representations of a liquid crystalline, azobenzene containing mesogen, simulated in the smectic and the isotropic phases. The out-of-plane dynamics in the smectic phase occurs via molecular hops from one smectic layer to the next. Hopping can occur via two mechanisms, with and without significant reorientation. The out-of-plane transport can be understood as a superposition of two (one associated with each mode of transport) independent continuous time random walks for which a single time-mapping factor would be rather inadequate. A comparison of the free-energy surfaces, relevant to the out-of-plane transport, qualitatively supports the above observations. Thus, this work underlines the need for building CG models that exhibit both structural and dynamical consistency to the underlying atomistic model. published

We propose an approach for summarizing the output of long simulations of complex systems, affording a rapid overview and interpretation. First, multidimensional scaling techniques are used in conjunction with dimension reduction methods to obtain a low-dimensional representation of the configuration space explored by the system. A nonparametric estimate of the density of states in this subspace is then obtained using kernel methods. The free energy surface is calculated from that density, and the configurations produced in the simulation are then clustered according to the topography of that surface, such that all configurations belonging to one local free energy minimum form one class. This topographical cluster analysis is performed using basin spanning trees which we introduce as subgraphs of Delaunay triangulations. Free energy surfaces obtained in dimensions lower than four can be visualized directly using iso-contours and -surfaces. Basin spanning trees also afford a glimpse of higher-dimensional topographies. The procedure is illustrated using molecular dynamics simulations on the reversible folding of peptide analoga. Finally, we emphasize the intimate relation of density estimation techniques to modern enhanced sampling algorithms. published

One of the major challenges in the development of coarse grained (CG) simulation models that aim at biomolecular structure formation processes is the correct representation of an environment-driven conformational change, for example, a folding/unfolding event upon interaction with an interface or upon aggregation. In the present study, we investigate this transferability challenge for a CG model using the example of diphenylalanine. This dipeptide displays a transition from a trans-like to a cis-like conformation upon aggregation as well as upon transfer from bulk water to the cyclohexane/water interface. Here, we show that one can construct a single CG model that can reproduce both the bulk and interface conformational behavior and the segregation between hydrophobic/hydrophilic medium. While the general strategy to obtain nonbonded interactions in the present CG model is to reproduce solvation free energies of small molecules representing the CG beads in the respective solvents, the success of the model strongly depends on nontrivial decisions one has to make to capture the delicate balance between the bonded and nonbonded interactions. In particular, we found that the peptide's conformational behavior is qualitatively affected by the cyclohexane/water interaction potential, an interaction that does not directly involve the peptide at all but merely influences the properties of the hydrophobic/hydrophilic interface. Furthermore, we show that a small modification to improve the structural/conformational properties of the CG model could dramatically alter the thermodynamic properties. (C) 2013 AIP Publishing LLC., Scientific and Technological Research Council of Turkey (TÜBİTAK); Max Planck Society; German Science Foundation

The macroscopic functionality of soft (bio-)materials is often triggered by quantum-mechanical events which are highly local in space and time. In order to arrive at the resulting macroscopically observable phenomena, many orders of magnitude need to be bridged on both the time and the length scale. In the present paper, we first introduce a range of simulation methods at different scales as well as theoretical approaches to form bridges between them. We then outline a strategy to develop an adaptive multiscale simulation approach which connects the quantum to the mesoscopic level by bringing together ab initio molecular dynamics (QM), classical (force field) molecular dynamics (MM), and coarse grained (CG) simulation techniques. With a multitude of photoactive materials in mind, we apply our methodology to a prototypical test case—light-induced phase transitions in a liquid crystal containing the azobenzene photoswitch. published

We discuss the development of a coarse-grained (CG) model for molecular dynamics (MD) simulation of a hydrophobic dipeptide, diphenylalanine, in aqueous solution. The peptide backbone is described with two CG beads per amino acid, the side groups and charged end groups are each described with one CG bead. In the derivation of interaction functions between CG beads we follow a bottom-up strategy where we devise potentials such that the resulting CG simulation reproduces the conformational sampling and the intermolecular interactions observed in an atomistic simulation of the same peptide. In the CG model, conformational flexibility of the peptide is accounted for through a set of intra-molecular (bonded) potentials. The approach followed to obtain the bonded potentials is discussed in detail. The CG potentials for nonbonded interactions are based on potentials of mean force obtained by atomistic simulations in aqueous solution. Following this approach, solvent mediation effects are included in the effective bead-bead nonbonded interactions and computationally very efficient (solvent-free) simulations of self-assembly processes can be performed. We show that the conformational properties of the all-atom dipeptide in explicit solvent can be accurately reproduced with the CG model. Moreover, preliminary simulations of peptide self-assembly performed with the CG model illustrate good agreement with results obtained from all-atom, explicit solvent simulations. published

In the previous paper [A. Villa, C. Peter, N. F. A. van der Vegt, Phys. Chem. Chem. Phys., 2009, DOI: 10.1039/b818144f], a strategy to develop a solvent-free coarse-grained model for peptides is outlined which is based on an atomistic (force field) description. The coarse-grained model is designed such that it correctly captures the conformational flexibility of the molecules and reproduces the interaction between peptides in aqueous solution. In the present paper, we revisit this model and present a method to devise nonbonded interactions such that also the coarse-grained level maintains explicit solvent degrees of freedom. In this new approach we rely on a structure-based coarse graining methodology which preserves the solvation structure around the peptides in combination with a method to devise nonbonded potentials between peptide beads in a way that the peptide–peptide interaction in water is represented correctly and that results in the correct thermodynamic association behavior. The outlined coarse graining strategy provides us with two (one implicit- and one explicit-solvent) models that are well suited for multiscale-simulation and scale-bridging purposes. We show that this is a powerful tool to efficiently simulate long time-scale and large length-scale biomolecular processes such as peptide self-assembly. In combination with an efficient backmapping methodology we can obtain well-equilibrated atomistic structures of the resulting aggregates.

While the determination of free-energy differences by MD simulation has become a standard procedure for which many techniques have been developed, total entropies and entropy differences are still hardly ever computed. An overview of techniques to determine entropy differences is given, and the accuracy and convergence behavior of five methods based on thermodynamic integration and perturbation techniques was evaluated using liquid water as a test system. Reasonably accurate entropy differences are obtained through thermodynamic integration in which many copies of a solute are desolvated. When only one solute molecule is involved, only two methods seem to yield useful results, the calculation of solute-solvent entropy through thermodynamic integration, and the calculation of solvation entropy through the temperature derivative of the corresponding free-energy difference. One-step perturbation methods seem unsuitable to obtain entropy estimates. published

An iterative algorithm based on fast-Fourier transforms is presented that solves the equations of continuum electrostatics for systems of heterogeneous dielectric permittivity (e.g., solute cavity in a solvent) under periodic boundary conditions. The method makes explicit use of the charge–dipole and dipole–dipole interaction tensors, and is thus applicable both to Coulombic interactions (Ewald scheme) and cutoff-based electrostatic interactions described by any polynomial function (including a Coulombic r−1 term), as commonly used in molecular dynamics simulations. The latter case includes, in particular, straight truncation of Coulombic interactions and truncation including a reaction-field correction. After testing and validation by comparison with existing methods, the algorithm is used to investigate the effect of cutoff truncation and artificial periodicity in explicit-solvent simulations of ionic solvation and ion–ion interactions. Both cutoff truncation and artificial periodicity are found to significantly affect the polarization around a spherical ion and its solvation free energy. The nature and magnitude of the two perturbations are analyzed in detail, and approximate analytical correction terms are derived to be applied to the results of explicit-solvent simulations. Cutoff truncation induces strong alterations in the potential of mean force for the interaction between two spherical ions. The present observations based on continuum electrostatics help to rationalize artifacts previously reported from explicit-solvent simulations involving cutoff truncation and, in particular, the unphysical attraction of like charges and repulsion of opposite charges, and the corresponding alterations in the relative stabilities of contact, solvent-separated, and free ion pairs. published

A new algorithm relying on finite integration is presented that solves the equations of continuum electrostatics for truncated (and possibly reaction-field corrected) solute–solvent and solvent–solvent interactions under either nonperiodic or periodic boundary conditions. After testing and validation by comparison with existing methods, the algorithm is applied to investigate the effect of cut-off truncation and artificial periodicity in explicit-solvent simulations of ionic solvation and ion–ion interactions. Both cut-off truncation and artificial periodicity significantly alter the polarization around a spherical ion and thus, its solvation free energy. The nature and magnitude of the two perturbations are analyzed in details, and correction terms are proposed for both effects. Cut-off truncation is also shown to induce strong alterations in the potential of mean force for ion–ion interaction. These observations help to rationalize artifacts previously observed in explicit–solvent simulations, namely spurious features in the radial distribution functions close to the cut-off distance and alterations in the relative stabilities of contact, solvent-separated and free ion pairs. published