Leonardo Darré

Transferable mixing of atomistic and coarse-grained water models.

Dual-resolution approaches for molecular simulations combine the best of two worlds, providing atomic details in regions of interest and coarser but much faster descriptions of less-relevant parts of molecular systems. Given the abundance of water in biomolecular systems, reducing the computational cost of simulating bulk water without perturbing the solutes properties is a very attractive strategy. Here we show that the coarse-grained model for water called WatFour (WT4) can be combined with any of the three most used water models for atomistic simulations (SPC, TIP3P, and SPC/E) without modifying the characteristics of the atomistic solvent and solutes. The equivalence of fully atomistic and hybrid solvation approaches is assessed by comparative simulations of pure water, electrolyte solutions, and the β1 domain of streptococcal protein G, for which comparisons between experimental and calculated chemical shifts at (13)Cα are equivalent.

SIRAH: A Structurally Unbiased Coarse-Grained Force Field for Proteins with Aqueous Solvation and Long-Range Electrostatics

Modeling of macromolecular structures and interactions represents an important challenge for computational biology, involving different time and length scales. However, this task can be facilitated through the use of coarse-grained (CG) models, which reduce the number of degrees of freedom and allow efficient exploration of complex conformational spaces. This article presents a new CG protein model named SIRAH, developed to work with explicit solvent and to capture sequence, temperature, and ionic strength effects in a topologically unbiased manner. SIRAH is implemented in GROMACS, and interactions are calculated using a standard pairwise Hamiltonian for classical molecular dynamics simulations. We present a set of simulations that test the capability of SIRAH to produce a qualitatively correct solvation on different amino acids, hydrophilic/hydrophobic interactions, and long-range electrostatic recognition leading to spontaneous association of unstructured peptides and stable structures of single polypeptides and protein-protein complexes.

Mixing Atomistic and Coarse Grain Solvation Models for MD Simulations: Let WT4 Handle the Bulk.

Accurate simulation of biomolecular systems requires the consideration of solvation effects. The arrangement and dynamics of water close to a solute are strongly influenced by the solute itself. However, as the solute-solvent distance increases, the water properties tend to those of the bulk liquid. This suggests that bulk regions can be treated at a coarse grained (CG) level, while keeping the atomistic details around the solute. Since water represents about 80% of any biological system, this approach may offer a significant reduction in the computational cost of simulations without compromising atomistic details. We show here that mixing the popular SPC water model with a CG model for solvation (called WatFour) can effectively mimic the hydration, structure, and dynamics of molecular systems composed of pure water, simple electrolyte solutions, and solvated macromolecules. As a nontrivial example, we present simulations of the SNARE membrane fusion complex, a trimeric protein-protein complex embedded in a double phospholipid bilayer. Comparison with a fully atomistic reference simulation illustrates the equivalence between both approaches.

Coarse-grained models of water

Coarse‐grained (CG) models for macromolecules have become a standard in the study of biological systems, overcoming limitations in size and time scales encountered by atomistic molecular dynamics simulations. Just as in any biomolecular ensemble, water in CG models plays a key role in mediating intermolecular and intramolecular interactions. However, owing to the highly nontrivial properties of water, important simplifications have been commonly used to treat solvation effects. Recent developments of CG models for water are overviewed, comparing some characteristic features and limitations.

Compaction of Duplex Nucleic Acids upon Native Electrospray Mass Spectrometry

We report on the fate of nucleic acids conformation in the gas phase as sampled using native mass spectrometry coupled to ion mobility spectrometry. On the basis of several successful reports for proteins and their complexes, the technique has become popular in structural biology, and the conformation survival becomes more and more taken for granted. Surprisingly, we found that DNA and RNA duplexes, at the electrospray charge states naturally obtained from native solution conditions (≥100 mM aqueous NH4OAc), are significantly more compact in the gas phase compared to the canonical solution structures. The compaction is observed for all duplex sizes (gas-phase structures are more compact than canonical B-helices by ∼20% for 12-bp, and by up to ∼30% for 36-bp duplexes), and for DNA and RNA alike. Molecular modeling (density functional calculations on small helices, semiempirical calculations on up to 12-bp, and molecular dynamics on up to 36-bp duplexes) demonstrates that the compaction is due to phosphate group self-solvation prevailing over Coulomb repulsion. Molecular dynamics simulations starting from solution structures do not reproduce the experimental compaction. To be experimentally relevant, molecular dynamics sampling should reflect the progressive structural rearrangements occurring during desolvation. For nucleic acid duplexes, the compaction observed for low charge states results from novel phosphate–phosphate hydrogen bonds formed across both grooves at the very late stages of electrospray.

Assessing the Accuracy of the SIRAH Force Field to Model DNA at Coarse Grain Level

We present a comparison between atomistic and coarse grain models for DNA developed in our group, which we introduce here with the name SIRAH. Molecular dynamics of DNA fragments performed using implicit and explicit solvation approaches show good agreement in structural and dynamical features with published state of the art atomistic simulations of double stranded DNA (using Amber and Charmm force fields). The study of the multi-microsecond timescale results in counterion condensation on DNA, in coincidence with high-resolution X-ray crystals. This result indicates that our model for solvation is able to correctly reproduce ionic strength effects, which are very difficult to capture by CG schemes.

Chapter 7:Molecular Modelling of Nucleic Acids

Nucleic acids (NAs) are biomolecules essential to all known forms of life that exhibit a remarkable structural and functional diversity. NAs are studied through several different techniques, including experimental and theoretical methods. The notorious improvements of the latter, together with the increased computation power, explain their widespread use in improving our understanding of their structure and function. Giving the multiscale nature of NAs, different theoretical disciplines like quantum chemistry, molecular mechanics and mesoscopic biophysical approaches are considered. In that regard, we describe and put into perspective, here, the most recent theoretical methods that have been used to study these biomolecules, from the electronic structure of nucleosides to the structural arrangements of chromosomes.

Dimerization confers increased stability to nucleases in 5′ halves from glycine and glutamic acid tRNAs

Abstract We have previously shown that 5′ halves from tRNAGlyGCC and tRNAGluCUC are the most enriched small RNAs in the extracellular space of human cell lines, and especially in the non-vesicular fraction. Extracellular RNAs are believed to require protection by either encapsulation in vesicles or ribonucleoprotein complex formation. However, deproteinization of non-vesicular tRNA halves does not affect their retention in size-exclusion chromatography. Thus, we considered alternative explanations for their extracellular stability. In-silico analysis of the sequence of these tRNA-derived fragments showed that tRNAGly 5′ halves can form homodimers or heterodimers with tRNAGlu 5′ halves. This capacity is virtually unique to glycine tRNAs. By analyzing synthetic oligonucleotides by size exclusion chromatography, we provide evidence that dimerization is possible in vitro. tRNA halves with single point substitutions preventing dimerization are degraded faster both in controlled nuclease digestion assays and after transfection in cells, showing that dimerization can stabilize tRNA halves against the action of cellular nucleases. Finally, we give evidence supporting dimerization of endogenous tRNAGlyGCC 5′ halves inside cells. Considering recent reports have shown that 5′ tRNA halves from Ala and Cys can form tetramers, our results highlight RNA intermolecular structures as a new layer of complexity in the biology of tRNA-derived fragments.