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.

Abstract

Due to poor stability and nature of low nuclease resistance of pure nucleic acids, a suitable chemical modification is required which improves several factors such as increased cellular uptake, altered duplex conformation and stability. In general, the modifications at ribose sugar (backbone) of the oligonucleotide attribute special features to the duplexes than other modifications. Some of the common modifications include 2'-O-methyl, 2'-O,4'-C-methylene-β-D-ribofuranosyl (LNA) and phosphoroamidate. The modified oligonucleotides have also been shown to be potential antisense agents. Molecular dynamics (MD) simulations are valuable tools to study nucleic acid dynamics, conformational preferences, stabilities etc. Here, we have employed different simulation techniques such as traditional MD, replica exchange MD to understand the properties of modified duplexes and also the origin for the effect of chemical modification. The simulations revealed several important aspects related to duplex stability and relation with their base content. The factors responsible for the stability/unstability of modified duplexes with different sequences are also examined. Our results also suggest that the differential changes observed in nucleic acids depends on the position, nature of the modified site. This study also provides a molecular level picture of structural changes arising due to different types of modifications which is important in designing antisense oligonucleotides.

Abstract

The structure and ion channel activity of the viral ion channels Vpu from human immunodeficiency virus type I (HIV-1) and 3a from SARS Coronavirus (SARS-CoV) have not been characterised in atomistic detail, in spite of the physiological importance of these ion channels. We have modelled several possible oligomeric states for Vpu, and carried out extensive molecular dynamics (MD) simulations in a lipid bilayer environment. Our results show that the pentamer is the most stable oligomeric form, with van der Waals interactions being the dominant force in holding together the monomeric units. The mechanism of ion conduction through the pentameric form has been investigated by umbrella sampling free energy calculations. We suggest that only one ion can pass through the channel at a time, rather than a continuous stream of ions; this is in agreement with experimental conductance studies [1]. We have also modelled possible structures for a monomeric unit of the ion channel SARS 3a, which has three helical transmembrane (TM) domains connected by loops [2]. Based on residue orientation, clusters of hydrophilic residues have been identified in each TM domain, and, by considering all possible orientations of these hydrophilic clusters, a number of monomers have been modelled and equilibrated in a membrane environment. We shall be presenting model structures of both monomeric and oligomeric states of 3a

Abstract

: Density functional B3LYP method was used to investigate the preference of intra and intermolecular cyclizations of linear tripeptides containing tetrahydrofuran amino acids. Two distinct model pathways were conceived for the cyclization reaction and all possible transition states and intermediates were located. Analysis of the energetics indicate intermolecular cyclization being favored by both thermodynamic and kinetic control. Geometric and NBO analyses were performed to explain the trends obtained along both the reaction pathways. Conceptual density functional theory based reactive indices also show that reaction pathways leading to intermolecular cyclization of the tripeptides are relatively more facile compared to intramolecular cyclization.

Abstract

t has been proposed that combining chemical and thermal denaturation along with mechanical unfolding enables better understanding of the thermodynamics of protein folding, and associated pathways. We have used molecular dynamics (MD) simulations, and umbrella sampling technique to study the effect of thermal and chemical perturbations on the unfolding of Trp-cage miniprotein (TC5b). Free energy profiles for the unfolding of the minicage protein were obtained at two different temperatures, and in presence and absence of urea. The distance between the penultimate terminal residues was used as the reaction coordinate for calculating the free energies. The unfolding involves opening of the Trp-cage, and separation of the secondary structure elements followed by the unfolding of the α-helix. Several energetic and geometric analyses including inter- and intramolecular interactions, and radial distribution functions and their relevance to the folding pathways will be discussed. Similar study on the titin I27 protein will also be presented.

Abstract

SAM-III riboswitch present in the 5’-UTR of mRNA that translates to SAM synthetase in certain bacteria is involved in regulating the biosynthesis of S-adenosylmethionine (SAM) by acting as an on-off switch for the translation process. We have used molecular dynamics (MD) and steered MD simulations to understand the ligand recognition and the switching mechanisms. Computations on model systems indicated that the riboswitch does not recognize SAM over a structurally related analog, S-adenosylhomocysteine (SAH). Nonetheless, the RNA uses nonspecific interactions to stabilize SAM in its binding pocket compared to SAH. Calculations were done in the absence of the ligand to examine the conformational changes responsible for the transition between on and off states. While the on- state is capable of sampling a large conformational space, formation of duplexlike structure comprising the adenine part of the ligand and sequentially distant nucleotides seems to be crucial for the on- to off- state transition.

Abstract

Vpu is an 81-residue protein encoded by human immunodeficiency virus type I (HIV-1) that facilitates viral release from host cells. The protein has a cytoplasmic domain and a helical transmembrane (TM) domain, of which the latter oligomerizes to form cation-specific ion channels. The number of TM domains that constitute the channel is still unclear, with experimental studies indicating the existence of a variety of oligomeric states. In this study, we have examined the possibility of Vpu to exist in tetra-, penta-, and hexameric states using comprehensive molecular dynamics (MD) simulations. By modeling the TM domain as an ideal α-helix, we carried out replica-exchange MD simulations in an implicit membrane environment for obtaining suitable starting structures, which were then subjected to extensive MD simulations in a fully hydrated lipid bilayer environment. The results show that the pentameric form is the most stable oligomeric state (the tetramer and hexamer models lose their initial channel-like structure), with helices in the pentamer being held together by strong van der Waals interactions. Hydrogen bonds between lipid headgroups and basic/hydrophilic residues on the protein are stronger in the pentamer than in the tetramer or the hexamer, indicating that these interactions might play a role in adhering the pentamer to the membrane. Free energy calculations using umbrella sampling technique have been performed to examine the potassium ion permeation through the pentameric pore. The results show a high free energy barrier corresponding to ion transport indicating weak ion channel activity in agreement with previous experimental biophysical studies.

Abstract

Chemical modifications on the backbone of the oligonucleotides have been shown to improve several factors such as increased cellular uptake, altered duplex conformation and stability. Modified oligonucleotides have also been shown to be potential antisense agents. Some of the common modifications include 2'-O-methyl, 2'-O,4'-C-methylene--D-ribofuranosyl (LNA) and phosphoroamidate. In general, the modifications at ribose sugar of the oligonucleotide attribute special features to the duplexes than other modifications. Molecular dynamics (MD) simulations are valuable tools to study their dynamics, conformational preferences, stabilities etc. Here, we have employed different simulation techniques such as classical MD, replica exchange MD to understand the impact of modification on the duplex properties. The simulations revealed several important aspects related to duplex stability and relation with their base content. Our results also suggest that the differential changes observed in nucleic acids depends on the position, nature of the modified site. This study also provides a molecular level picture for the origin of structural changes arise due to different types of modifications which is very important in designing the most fruitful antisense oligonucleotides.

Abstract

Here, we present an update of the CHARMM27 all-atom additive force field for nucleic acids that improves the treatment of RNA molecules. The original CHARMM27 force field parameters exhibit enhanced Watson-Crick base pair opening which is not consistent with experiment, whereas analysis of molecular dynamics (MD) simulations show the 2'-hydroxyl moiety to almost exclusively sample the O3' orientation. Quantum mechanical (QM) studies of RNA related model compounds indicate the energy minimum associated with the O3' orientation to be too favorable, consistent with the MD results. Optimization of the dihedral parameters dictating the energy of the 2'-hydroxyl proton targeting the QM data yielded several parameter sets, which sample both the base and O3' orientations of the 2'-hydroxyl to varying degrees. Selection of the final dihedral parameters was based on reproduction of hydration behavior as related to a survey of crystallographic data and better agreement with experimental NMR Jcoupling values. Application of the model, designated CHARMM36, to a collection of canonical and noncanonical RNA molecules reveals overall improved agreement with a range of experimental observables as compared to CHARMM27. The results also indicate the sensitivity of the conformational heterogeneity of RNA to the orientation of the 2'-hydroxyl moiety and support a model whereby the 2'- hydroxyl can enhance the probability of conformational transitions in RNA.