The G\=oMartini approach: Revisiting the concept of contact maps and the modelling of protein complexes

We present a review of a series of contact maps for the determination of native interactions in proteins and nucleic acids based on a distance-threshold. Such contact maps are mostly based on physical and chemical construction, and yet they are sensitive to some parameters (e.g. distances or atomic radii) and can neglect some key interactions. Furthermore, we also comment on a new class of contact maps that only requires geometric arguments. The contact map is a necessary ingredient to build a robust G\=oMartini model for proteins and their complexes in the Martini 3 force field. We present the extension of a popular structure-based G\=o-like approach for the study of protein-sugar complexes, and also limitations of this approach are discussed. The G\=oMartini approach was first introduced by Poma et al. J. Chem. Theory Comput. 2017, 13(3), 1366-1374 in Martini 2 force field and recently, it has gained the status of gold-standard for protein simulation undergoing conformational changes in Martini 3 force field. We discuss several studies that have provided support to this approach in the context of the biophysical community.Comment: 19 pages, 3 figure

Effects and limitations of a nucleobase-driven backmapping procedure for nucleic acids using steered molecular dynamics

Coarse-grained models can be of great help to address the problem of structure prediction in nucleic acids. On one hand they can make the prediction more efficient, while on the other hand they can also help to identify the essential degrees of freedom and interactions for the description of a number of structures. With the aim to provide an all-atom representation in an explicit solvent to the predictions of our SPlit and conQueR (SPQR) coarse-grained model of RNA, we recently introduced a backmapping procedure which enforces the predicted structure into an atomistic one by means of steered molecular dynamics. These simulations minimize the ERMSD, a particular metric which deals exclusively with the relative arrangement of nucleobases, between the atomistic representation and the target structure. In this paper, we explore the effects of this approach on the resulting interaction networks and backbone conformations by applying it on a set of fragments using as a target their native structure. We find that the geometry of the target structures can be reliably recovered, with limitations in the regions with unpaired bases such as bulges. In addition, we observe that the folding pathway can also change depending on the parameters used in the definition of the ERMSD and the use of other metrics such as the RMSD

Unravelling interspecific relationships among highland lizards: First phylogenetic hypothesis using total evidence of the Liolaemus montanus group (Iguania: Liolaemidae)

The South American lizard genus Liolaemus comprises > 260 species, of which > 60 are recognized as members of the Liolaemus montanus group, distributed throughout the Andes in central Peru, Bolivia, Chile and central Argentina. Despite its great morphological diversity and complex taxonomic history, a robust phylogenetic estimate is still lacking for this group. Here, we study the morphological and molecular diversity of the L. montanus group and present the most complete quantitative phylogenetic hypothesis for the group to date. Our phylogeny includes 103 terminal taxa, of which 91 are members of the L. montanus group (58 are assigned to available species and 33 are of uncertain taxonomic status). Our matrix includes 306 morphological and ecological characters and 3057 molecular characters. Morphological characters include 48 continuous and 258 discrete characters, of which 70% (216) are new to the literature. The molecular characters represent five mitochondrial markers. We performed three analyses: A morphology-only matrix, a molecular-only matrix and a matrix including both morphological and molecular characters (total evidence hypothesis). Our total evidence hypothesis recovered the L. montanus group as monophyletic and included ≥ 12 major clades, revealing an unexpectedly complex phylogeny.Fil: Abdala, Cristian Simón. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; ArgentinaFil: Quinteros, Andres Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Semhan, Romina Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; ArgentinaFil: Bulacios Arroyo, Ana Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; ArgentinaFil: Schulte, James. Belloit College; Estados UnidosFil: Paz, Marcos Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; ArgentinaFil: Ruiz Monachesi, Mario Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Laspiur, Julio Alejandro. Universidad Nacional de San Juan. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; ArgentinaFil: Aguilar Kirigin, Alvaro Juan. Colección Boliviana de Fauna; Bolivia. Universidad Mayor de San Andrés; BoliviaFil: Gutierrez Poblete, Ricardo. Universidad Nacional de San Agustín. Facultad de Ciencias Biológicas. Departamento Académico de Biología. Museo de Historia Natural; PerúFil: Valladares Faundez, Pablo. Universidad de Tarapaca.; ChileFil: Valdes, José Julian. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Portelli, Sabrina Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Bio y Geociencias del NOA. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Museo de Ciencias Naturales. Instituto de Bio y Geociencias del NOA; ArgentinaFil: Santa Cruz, Roy. Universidad Nacional de San Agustín. Facultad de Ciencias Biológicas. Departamento Académico de Biología. Museo de Historia Natural; PerúFil: Aparicio, James. Colección Boliviana de Fauna; Bolivia. Universidad Mayor de San Andrés; BoliviaFil: García, Noelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; ArgentinaFil: Langstroth, Robeert. Colección Boliviana de Fauna; Bolivia. Universidad Mayor de San Andrés; Bolivi

A nucleobase-centered coarse-grained representation for structure prediction of RNA motifs

We introduce the SPlit-and-conQueR (SPQR) model, a coarse-grained (CG) representation of RNA designed for structure prediction and refinement. In our approach, the representation of a nucleotide consists of a point particle for the phosphate group and an anisotropic particle for the nucleoside. The interactions are, in principle, knowledge-based potentials inspired by the $\mathcal E$SCORE function, a base-centered scoring function. However, a special treatment is given to base-pairing interactions and certain geometrical conformations which are lost in a raw knowledge-based model. This results in a representation able to describe planar canonical and non-canonical base pairs and base-phosphate interactions and to distinguish sugar puckers and glycosidic torsion conformations. The model is applied to the folding of several structures, including duplexes with internal loops of non-canonical base pairs, tetraloops, junctions and a pseudoknot. For the majority of these systems, experimental structures are correctly predicted at the level of individual contacts. We also propose a method for efficiently reintroducing atomistic detail from the CG representation

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview

With both catalytic and genetic functions, ribonucleic acid (RNA) is perhaps the most pluripotent chemical species in molecular biology, and its functions are intimately linked to its structure and dynamics. Computer simulations, and in particular atomistic molecular dynamics (MD), allow structural dynamics of biomolecular systems to be investigated with unprecedented temporal and spatial resolution. We here provide a comprehensive overview of the fast-developing field of MD simulations of RNA molecules. We begin with an in-depth, evaluatory coverage of the most fundamental methodological challenges that set the basis for the future development of the field, in particular, the current developments and inherent physical limitations of the atomistic force fields and the recent advances in a broad spectrum of enhanced sampling methods. We also survey the closely related field of coarse-grained modeling of RNA systems. After dealing with the methodological aspects, we provide an exhaustive overview of the available RNA simulation literature, ranging from studies of the smallest RNA oligonucleotides to investigations of the entire ribosome. Our review encompasses tetranucleotides, tetraloops, a number of small RNA motifs, A-helix RNA, kissing-loop complexes, the TAR RNA element, the decoding center and other important regions of the ribosome, as well as assorted others systems. Extended sections are devoted to RNA-ion interactions, ribozymes, riboswitches, and protein/RNA complexes. Our overview is written for as broad of an audience as possible, aiming to provide a much-needed interdisciplinary bridge between computation and experiment, together with a perspective on the future of the field

Hydrodynamics of discrete-particle models of spherical colloids: A multiparticle collision dynamics simulation study

We investigate the hydrodynamic properties of a spherical colloid model, which is composed of a shell of point particles by hybrid mesoscale simulations, which combine molecular dynamics simulations for the sphere with the multiparticle collision dynamics approach for the fluid. Results are presented for the center-of-mass and angular velocity correlation functions. The simulation results are compared with theoretical results for a rigid colloid obtained as a solution of the Stokes equation with no-slip boundary conditions. Similarly, analytical results of a point-particle model are presented, which account for the finite size of the simulated system. The simulation results agree well with both approaches on appropriative time scales; specifically, the long-time correlations are quantitatively reproduced. Moreover, a procedure is proposed to obtain the infinite-system-size diffusion coefficient based on a combination of simulation results and analytical predictions. In addition, we present the velocity field in the vicinity of the colloid and demonstrate its close agreement with the theoretical prediction. Our studies show that a point-particle model of a sphere is very well suited to describe the hydrodynamic properties of spherical colloids, with a significantly reduced numerical effort

Structural 3D Domain Reconstruction of the RNA Genome from Viruses with Secondary Structure Models

Three-dimensional RNA domain reconstruction is important for the assembly, disassembly and delivery functionalities of a packed proteinaceus capsid. However, to date, the self-association of RNA molecules is still an open problem. Recent chemical probing reports provide, with high reliability, the secondary structure of diverse RNA ensembles, such as those of viral genomes. Here, we present a method for reconstructing the complete 3D structure of RNA genomes, which combines a coarse-grained model with a subdomain composition scheme to obtain the entire genome inside proteinaceus capsids based on secondary structures from experimental techniques. Despite the amount of sampling involved in the folded and also unfolded RNA molecules, advanced microscope techniques can provide points of anchoring, which enhance our model to include interactions between capsid pentamers and RNA subdomains. To test our method, we tackle the satellite tobacco mosaic virus (STMV) genome, which has been widely studied by both experimental and computational communities. We provide not only a methodology to structurally analyze the tertiary conformations of the RNA genome inside capsids, but a flexible platform that allows the easy implementation of features/descriptors coming from both theoretical and experimental approaches

Inter-Dye Distance Distributions Studied by a Combination of Single-Molecule FRET-Filtered Lifetime Measurements and a Weighted Accessible Volume (wAV) Algorithm

Förster resonance energy transfer (FRET) is an important tool for studying the structural and dynamical properties of biomolecules. The fact that both the internal dynamics of the biomolecule and the movements of the biomolecule-attached dyes can occur on similar timescales of nanoseconds is an inherent problem in FRET studies. By performing single-molecule FRET-filtered lifetime measurements, we are able to characterize the amplitude of the motions of fluorescent probes attached to double-stranded DNA standards by means of flexible linkers. With respect to previously proposed experimental approaches, we improved the precision and the accuracy of the inter-dye distance distribution parameters by filtering out the donor-only population with pulsed interleaved excitation. A coarse-grained model is employed to reproduce the experimentally determined inter-dye distance distributions. This approach can easily be extended to intrinsically flexible proteins allowing, under certain conditions, to decouple the macromolecule amplitude of motions from the contribution of the dye linkers

Static and dynamic light scattering by red blood cells: A numerical study

Light scattering is a well-established experimental technique, which gains more and more popularity in the biological field because it offers the means for non-invasive imaging and detection. However, the interpretation of light-scattering signals remains challenging due to the complexity of most biological systems. Here, we investigate static and dynamic scattering properties of red blood cells (RBCs) using two mesoscopic hydrodynamics simulation methods—multi-particle collision dynamics and dissipative particle dynamics. Light scattering is studied for various membrane shear elasticities, bending rigidities, and RBC shapes (e.g., biconcave and stomatocyte). Simulation results from the two simulation methods show good agreement, and demonstrate that the static light scattering of a diffusing RBC is not very sensitive to the changes in membrane properties and moderate alterations in cell shapes. We also compute dynamic light scattering of a diffusing RBC, from which dynamic properties of RBCs such as diffusion coefficients can be accessed. In contrast to static light scattering, the dynamic measurements can be employed to differentiate between the biconcave and stomatocytic RBC shapes and generally allow the differentiation based on the membrane properties. Our simulation results can be used for better understanding of light scattering by RBCs and the development of new non-invasive methods for blood-flow monitoring

Single-Molecule FRET Measurements in Additive-Enriched Aqueous Solutions

The addition of high amounts of chemical denaturants, salts, viscosity enhancers or macro-molecular crowding agents has an impact on the physical properties of buffer solutions. Among others, the (microscopic) viscosity, the refractive index, the dielectric constant, and the ionic strength can be affected. Here, we systematically evaluate the importance of solvent characteristics with respect to single-molecule FRET (smFRET) data. First, we present a confocal based method for the determination of fluorescence quantum yields to facilitate a fast characterization of smFRET-samples at sub-nM-concentrations. As a case study, we analyze smFRET data of structurally rigid, double-stranded DNA-oligonucleotides in aqueous buffer and in buffers with specific amounts of glycerol, guanidine hydrochloride (GdnHCl), and sodium chloride (NaCl) added. We show that the calculation of interdye distances, without taking into account solvent-induced spectral and photophysical changes of the labels, leads to deviations of up to 4 Å from the real interdye distances. Additionally, we demonstrate that electrostatic dye–dye repulsions are negligible for the interdye distance regime considered here (>50 Å). Finally, we use our approach to validate the further compaction of the already unfolded state of phosphoglycerate kinase (PGK) with decreasing denaturant concentrations, a mechanism known as coil–globule transition