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 (WC) base pair opening which is not consistent with experiment while analysis of MD simulations show the 2′-hydroxyl moiety to almost exclusively sample the O3′ orientation. Quantum mechanical 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 J-coupling values. Application of the model, designated CHARMM36, to a collection of canonical and non-canonical 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.

Application of deep learning techniques for de novo generation of molecules, termed as inverse molecular design, has been gaining enormous traction in drug design. The representation of molecules in SMILES notation as a string of characters enables the usage of state of the art models in natural language processing, such as Transformers, for molecular design in general. Inspired by generative pre-training (GPT) models that have been shown to be successful in generating meaningful text, we train a transformer-decoder on the next token prediction task using masked self-attention for the generation of druglike molecules in this study. We show that our model, MolGPT, performs on par with other previously proposed modern machine learning frameworks for molecular generation in terms of generating valid, unique, and novel molecules. Furthermore, we demonstrate that the model can be trained conditionally to control multiple properties of the generated molecules. We also show that the model can be used to generate molecules with desired scaffolds as well as desired molecular properties by conditioning the generation on scaffold SMILES strings of desired scaffolds and property values. Using saliency maps, we highlight the interpretability of the generative process of the model.

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Urea has long been used to probe the stability and folding kinetics of proteins. 1 In contrast only recently it was shown that the RNA molecules that have a high propensity to misfold can be resolved using moderate amounts of urea. 2 Urea titrations can also be used to probe the interactions that stabilize the folded states of RNA. 2c Although the mechanism by which urea denatures proteins is now fairly well understood 3 the nature of interactions by which urea destabilizes RNA is not known. In order to provide a microscopic basis for the action of urea on RNA we have carried out extensive all atom molecular dynamics (MD) simulations on two RNA constructs using two urea force fields. Destabilization of RNA is due to disruption of base-pair interactions by direct hydrogen bonding of urea with the bases. The simulations also reveal a novel mechanism in which urea molecules engage in stacking interactions with the purine bases. 4 Analyses of 20 ns trajectories generated using MD simulations with a urea force field that was created as a part of the present work (see SI for simulation details, SI Figs. 1 and 2 and Tables 1-3 for urea parameter development, and for assessing the validity of the force field) of the 22-nucleotide RNA hairpin P5GA 5 (Fig. 1A) in various urea concentrations ([C]s) reveal that at high [C] the solvent-exposed stem regions lead to disruption of base pairing. The fraction of intact hydrogen bonds associated with the bases in the stem decreases from about 0.71 in the absence of urea to 0.46 in 8M urea. The loss of the Watson-Crick (WC) hydrogen bonds is accompanied by opening of the base pairs, which is reflected in the distribution of the hydrogen bond donor-acceptor distances (R HB ) in the hairpin stem (Fig. 1B). The base-paired state is indicated by a sharp peak at R HB = 3Å, whose height decreases as [C] increases to 6M. The probability of sampling R HB distances that are greater than 10Å (Fig. 1B) increases greatly in high [C], which results in a rotation of the bases of the helix leading to N1-N3 distances of about 16Å. 6 Examination of opening at the individual base pair level reveals considerable heterogeneity 7 with the largest fluctuations occurring at the GA and GU mismatches. We also show that urea-induced disruption of the base opening due to the loss of WC hydrogen bonds is nonspecific in the sense that urea does not preferentially interact with a specific base pair. These finding suggests that denaturation of RNA is due to favorable non-specific interactions with amide-like surfaces of the nucleic acids. The average base-base interaction energies (GC, thirum@umd.edu. amackere@rx.umaryland Table 4). When averaged over all base pair interactions in the stem the interactions become less favorable by about 2.7 kcal/mol at 6M relative to [C] = 0 (SI Table 4). The average interaction energies for certain base pairs (for example A6G17 and U8A15) are substantially less at high [C] relative to their values in water (see SI Table 4).In contrast, the backbone conformational proper...

Ab initio (MP2, CCSD(T)) and hybrid density functional theory (B3LYP) calculations with up to triple-ζ basis set were done to locate all possible minima, where each carbon in the molecule is tetracoordinate, on the C6H6 potential energy surface. The search was initiated with a total of 218 structures, and in few cases, geometrical and stereoisomers were considered. The exhaustive study on all these topological structures resulted in a total of 263 stationary points on the C6H6 potential energy surface. The B3LYP level characterizes 209 as minima, 31 as transition states, 8 as second-order, 7 as third-order, and 1 as fourth-order saddle points. The remaining 7 structures could be located as stationary points only at the MP2 level. The molecules were classified into acyclic, monocyclic, bicyclic, tricyclic, and tetracyclic. The acyclic isomers fall within a range of 60−80 kcal/mol higher in energy compared to benzene. Among the cyclic structures, the range of relative stabilities of minima is larger, viz., monocyclic (31−146 kcal/mol), bicyclic (72−159 kcal/mol), tricyclic (72−300 kcal/mol), and tetracyclic (102−156 kcal/mol). Strain due to small three and four membered rings and constrained double and triple bonds control the relative stabilities of these isomers. The computed isomers exhibit various novel bonding modes for carbon, namely, planar tetracoordinate, hypervalent, pyramidal, bent/twisted double bonds, vicinal dicarbenes, nonlinear triple bonds, and so forth. Absolute chemical hardness values have no correlation with the relative stabilities, and about 45 molecules have higher hardness values than that of benzene.

The optical activity of a metal nanocluster (NC) is induced either by an asymmetric arrangement of constituents or by a dissymmetric field of a chiral ligand layer. Herein, we unveil the origin of chirality in Ag 29 NCs, which is attributed to the intrinsically chiral atomic arrangement. The X-ray crystal structure of a Ag 29 (BDT) 12 (TPP) 4 NC (BDT: 1,3-benzenedithiol; TPP: triphenylphosphine) manifested the presence of intrinsic chirality in the outer shell capping the icosahedral achiral Ag 13 core. The enantiomers of the Ag 29 (BDT) 12 (TPP) 4 NC are separated by high-performance liquid chromatography (HPLC) using a chiral column for the first time, showing mirror-image circular dichroism (CD) spectra. The CD spectra are reproduced by time-dependent density functional theory (TDDFT) calculations based on enantiomeric Ag 29 models with achiral 1,3-propanedithiolate ligands. The mechanism of chiral induction in the synthesis of Ag 29 (DHLA) 12 (DHLA: a-dihydrolipoic acid) NCs with a chiral ligand system is further discussed with the aid of DFT calculations. The use of the enantiomeric DHLA ligand preferentially leads to a one-handed atomic arrangement which is more stable than the opposite one, inducing the enantiomeric excess in the population of intrinsically chiral Ag 29 NCs with CD activity.

Riboswitches are RNA-based genetic control elements that function via a conformational transition mechanism when a specific target molecule binds to its binding pocket. To facilitate an atomic detail interpretation of experimental investigations on the role of the adenine ligand on the conformational properties and kinetics of folding of the add adenine riboswitch, molecular dynamics (MD) simulations were performed in both the presence and absence of the ligand. In the absence of ligand, structural deviations were observed in the J23 junction and the P1 stem. Destabilization of the P1 stem in the absence of ligand involves the loss of direct stabilizing interactions with the ligand, with additional contributions from the J23 junction region. The J23 junction of the riboswitch is found to be more flexible and the tertiary contacts among the junction regions are altered in the absence of the adenine ligand; results suggest that the adenine ligand associates and dissociates from the riboswitch in the vicinity of J23. Good agreement was obtained with the experimental data with the results indicating dynamic behavior of the adenine ligand on the nanosecond timescale to be associated with the dynamic behavior of hydrogen bonding with the riboswitch. Results also predict that direct interactions of the adenine ligand with U74 of the riboswitch are not essential for stable binding even though it is crucial for its recognition. The possibility of methodological artifacts and force field inaccuracies impacting the present observations was checked by additional MD simulations in the presence of 2,6-diaminopurine and in the crystal environment.

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