Abstract

DNA–RNA hybrids are heterogeneous nucleic acid duplexes consisting of a DNA strand and a RNA strand, and are formed as key intermediates in many important biological processes. They serve as substrates for the RNase H enzymatic activity, which has been exploited for several biomedical technologies such as antiviral and antisense therapies. To understand the relation of structural properties with the base composition in DNA–RNA hybrids, molecular dynamics (MD) simulations were performed on selected model systems by systematically varying the deoxypyrimidine (dPy) content from 0 to 100% in the DNA strand. The results suggest that the hybrid duplex properties are highly dependent on their deoxypyrimidine content of the DNA strand. However, such variations are not seen in their corresponding pure DNA and RNA duplex counterparts. It is also noticed that the systematic variation in deoxypyrimidine …

Abstract

Gold cluster–nucleobase complexes have potential applications in designing and fabrication of novel electronic nano-devices, and there has been a surge in research activities in this area recently. Binding of gold clusters (Au3 and Au4) with DNA bases and size-expanded DNA bases (x-bases) have been studied using density functional theory employing high quality basis set. A comprehensive attempt has been made to examine several gold–nucleobase complexes with respect to change in the orientation of Au clusters with respect to all the titratable sites of the bases. Geometric and electronic features of these complexes provided evidences for existence of non-conventional hydrogen bonds, which was further substantiated via vibrational frequency and natural bond orbital (NBO) analysis. The nucleobases, both canonical and size-expanded forms, form stable complexes with both the gold clusters considered …

Abstract

The viral protein U (Vpu) encoded by HIV-1 has been shown to assist in the detachment of virion particles from infected cells. Vpu forms cation-specific ion channels in host cells, and has been proposed as a potential drug target. An understanding of the mechanism of ion transport through Vpu is desirable, but remains limited because of the unavailability of an experimental structure of the channel. Using a structure of the pentameric form of Vpu – modeled and validated based on available experimental data – umbrella sampling molecular dynamics simulations (cumulative simulation time of more than 0.4 µs) were employed to elucidate the energetics and the molecular mechanism of ion transport in Vpu. Free energy profiles corresponding to the permeation of Na+ and K+ were found to be similar to each other indicating lack of ion selection, consistent with previous experimental studies. The Ser23 residue is shown to enhance ion transport via two mechanisms: creating a weak binding site, and increasing the effective hydrophilic length of the channel, both of which have previously been hypothesized in experiments. A two-dimensional free energy landscape has been computed to model multiple ion permeation, based on which a mechanism for ion conduction is proposed. It is shown that only one ion can pass through the channel at a time. This, along with a stretch of hydrophobic residues in the transmembrane domain of Vpu, explains the slow kinetics of ion conduction. The results are consistent with previous conductance studies that showed Vpu to be a weakly conducting ion channel.

Abstract

Archaeal chromatin proteins share molecular and functional similarities with both bacterial and eukaryotic chromatin proteins. These proteins play an important role in functionally organizing the genomic DNA into a compact nucleoid. Cren7 and Sul7 are two crenarchaeal nucleoidassociated proteins, which are structurally homologous, but not conserved at the sequence level. Cocrystal structures have shown that these two proteins induce a sharp bend on binding to DNA. In this study, we have investigated the architectural properties of these proteins using atomic force microscopy, molecular dynamics simulations and magnetic tweezers. We demonstrate that Cren7 and Sul7 both compact DNA molecules to a similar extent. Using a theoretical model, we quantify the number of individual proteins bound to the DNA as a function of protein concentration and show that forces up to 3.5 pN do not affect this binding. Moreover, we investigate the flexibility of the bending angle induced by Cren7 and Sul7 and show that the protein–DNA complexes differ in flexibility from analogous bacterial and eukaryotic DNA-bending proteins.

Abstract

The effect of the linker length (–CH2–) connecting the diene and the dienophile in macrocyclic trienes on their transannular Diels–Alder (TADA) reactivity has been investigated using density functional theory (DFT) calculations. The relationship between the conformational properties of these reactants and their reaction energy barriers was examined and a quantitative relationship has been obtained. The transition state energy barriers were found to increase with an increase in the linker length, which is in contrast to the expected trend. The conformational preferences of the triene reactants were studied using replica exchange molecular dynamics (REMD) simulations. These calculations reveal that longer linkers lead to a decreased probability of the occurrence of conformations with the diene and dienophile parts of the system vicinal to each other, and thus lower reactivity of systems with long linkers. Excellent correlations between the transition state energies and the cumulative probabilities corresponding to a short distance between the reactive sites, along with the ability of the diene to exist in the s-cisoid form, were observed.

Abstract

Locked nucleic acid (LNA) is a chemical modification which introduces a -O-CH2-linkage in the furanose sugar of nucleic acids and blocks its conformation in a particular state. Two types of modifications, namely, 2'-O,4'-C-methylene-β-D-ribofuranose (β-D-LNA) and 2'-O,4'-C-methylene-α-L-ribofuranose (α-L-LNA), have been shown to yield RNA and DNA duplex-like structures, respectively. LNA modifications lead to increased melting temperatures of DNA and RNA duplexes, and have been suggested as potential therapeutic agents in antisense therapy. In this study, molecular dynamics (MD) simulations were performed on fully modified LNA duplexes and pure DNA and RNA duplexes sharing a similar sequence to investigate their structure, stabilities, and solvation properties. Both LNA duplexes undergo unwinding of the helical structure compared to the pure DNA and RNA duplexes. Though the α-LNA substituent has been proposed to mimic deoxyribose sugar in its conformational properties, the fully modified duplex was found to exhibit unique structural and dynamic properties with respect to the other three nucleic acid structures. Free energy calculations accurately capture the enhanced stabilization of the LNA duplex structures compared to DNA and RNA molecules as observed in experiments. π-stacking interaction between bases from complementary strands is shown to be one of the contributors to enhanced stabilization upon LNA substitution. A combination of two factors, namely, nature of the -O-CH2- linkage in the LNAs vs their absence in the pure duplexes and similar conformations of the sugar rings in DNA and α-LNA vs the other two, is suggested to contribute to the stark differences among the four duplexes studied here in terms of their structural, dynamic, and energetic properties

Abstract

The emergence of single-molecule force measurement experiments has facilitated a better understanding of protein folding pathways and the thermodynamics involved. Computational methods such as steered molecular dynamics (SMD) simulations are helpful in providing atomistic level information on the unfolding pathways. Recent experimental studies have showed that combinations of single-molecule experiments with traditional methods such as chemical and/or thermal denaturation yield additional insights into the folding phenomenon. In this study, we report results from extensive computations (a total of about 60 SMD simulations with a total length of about 0.4 μs) that address the effect of thermal perturbation on the mechanical stability of the I27 domain of the protein titin. A wide range of temperatures (280–340 K) were considered for the pulling, which was done at both constant velocity and constant force using SMD simulations. Good agreement with experimental data, such as for the trends in changes in average force and the maximum force with respect to the temperature, was obtained. This study identifies two competing pathways for the mechanical unfolding of I27, and illustrates the significance of combining various techniques to examine protein foldin

Abstract

The role of salt bridges in chromatin protein Sso7d, from S. solfataricus has previously been shown to be crucial for its unusual high thermal stability. Experimental studies have shown that single site mutation of Sso7d (F31A) leads to a substantial decrease in the thermal stability of this protein due to distortion of the hydrophobic core. In the present study, we have performed a total of 0.2s long molecular dynamics (MD) simulations on F31A at room temperature, and at 360 K, close to the melting temperature of the wild type (WT) protein to investigate the role of hydrophobic core on protein stability. Sso7d-WT was shown to be stable at both 300 and 360 K; however, F31A undergoes denaturation at 360 K, consistent with experimental results. The structural and energetic properties obtained using the analysis of MD trajectories indicate that the single mutation results in high flexibility of the protein, and loosening of intramolecular interactions. Correlation between the dynamics of the salt bridges with the structural transitions and the unfolding pathway indicate the importance of both salt bridges and hydrophobic in effecting thermal stability of proteins in general.

Abstract

A series of dihydrogen complexes trans-[Ru(η2-H2){SC(SR)H}(dppe)2][X][BF4] (R = CH3, X = OTf; R = C6H5CH2, X = BPh4; R = H2C=CHCH2, X = BPh4; dppe = Ph2PCH2CH2PPh2) bearing sulfur-donor ligands has been synthesized by protonation of the (alkyl dithioformate)hydrido complexes trans-[Ru(H){SC(SR)H}(dppe)2][X] by using HBF4•Et2O. Competitive substitution reactions between H2 and SC(SR)H in trans-[Ru(η2-H2){SC(SR)H}(dppe)2][X][BF4] have been studied by treatment with CH3CN, CO, and P(OCH3)3. These resulted in the expulsion of SC(SR)H from the metal center, thus indicating that the alkyl dithioformate ligand is more labile than H2. Bonding of alkyl dithioformate ligands (sulfur-donor ligands) trans to H2 have been studied by comparing the H–H distances and chemical-shift values (1H NMR spectroscopy) of the various dihydrogen complexes bearing different trans ligands. This study qualitatively suggests that the alkyl dithioformate ligands in these trans-dihydrogen complexes show a poor π effect, and it is further supported by density functional theory calculations. The first example of a dihydrogen complex bearing dithioformic acid, trans-[Ru(η2-H2){SC(SH)H}(dppe)2][BF4]2, was obtained by protonation of trans-[Ru(H){SC(S)H}(dppe)2] by using HBF4•Et2O.

Abstract

In the late 19th century, van’t Hoff and Le Bel proposed that carbon prefers a tetrahedral arrangement in its tetracoordinate form. Similarly, the isoelectronic species such as B-, N+, Al-, Si and P+ assume tetrahedral arrangement. However, it has been shown by several research groups that planar arrangement for tetracoordinated carbon centers may be possible for certain molecules that are stabilized by steric constraints and electronic effects. Sastry and coworkers have identified a series of neutral hydrocarbons that are stable in their planar form. We have done high level quantum chemical calculations on skeletally substituted derivative of one of the hydrocarbons (C5H4). Interestingly, the phosphonium ion (C4PH4 +) is found to be a minimum on its potential energy surface consistently by both density functional theory and MP2 methods. A transition state corresponding to the interconversion between the two forms was identified, which indicates rapid transitions. Additionally, the tetrahedral form was found to be the minima for C and B-. The tetrahedral form is the minima for Al- and Si, whereas the planar form was characterized as a transition state that connects two identical tetrahedral forms. Ab initio molecular dynamics calculations indicate that C4H4Si does undergo rapid interconversion between two identical tetrahedral structures through the planar transition state in the femtosecond timescale. However, C4H4P+ and C4H4Al- undergoes irreversible ring opening during the simulations. These molecules/ions were further analyzed using NICS calculations and ring opening reactivities.