Mutation-Induced Conformational Changes and Energetics for Binding of FMN Ligand in Flavin Mononucleotide Riboswitch by Molecular Dynamics Simulations

Riboswitches are the type of regulatory elements present in the untranslated region of mRNA and specifically bind to the natural ligand to regulate gene expression. This binding specificity can be affected by even single point mutation incorporated in the core of the riboswitch. In this work, we have examined the mutations at the binding site residue in Flavin Mononucleotide (FMN) riboswitch structure with 30ns molecular dynamics simulations. The interaction of ligand (FMN) with riboswitch has been characterized using root mean square deviation, hydrogen bonding analysis, and the calculated binding affinities. Mutation at A48G and G62U show the enhanced binding energy however, the mutation at A85G, are energetically unfavorable compared to the wild type. This work gives valuable insight into the structures and energetics of the mutated FMN riboswitch to design new hits for biological applications. This work is licensed under a Creative Commons Attribution 4.0 International License

Solvent Effects on the Stereoselectivity of Reaction of Methyl Acrylate, Methyl Methacrylate and Methyl trans-Crotonate with Cyclopentadiene: A Computational Study

The stereoselectivity of reaction of methyl acrylate, methyl methacrylate and methyl transcrotonate with cyclopentadiene was studied with ab initio RHF/6-31G* and B3LYP/6-31G* levels of theory. The stereoselectivities predicted for methyl acrylate and methyl methacrylate with cyclopentadiene in the gas phase were found to be in good agreement with experimental results. The preference of endo selectivity in solvents was more pronounced for methyl acrylate, however, the preference for the exo-addition for methyl methacrylate was predicted to be reduced in solvents. The solvent calculations predicted the endo- preference for methyl trans-crotonate in agreement with the experimental observations. The lower endo selectivity for methyl trans-crotonate with cyclopentadiene seems to be governed by the degree of asynchronicity of endo- and exo-transition states in water. B3LYP/6-31G* calculated activation enthalpy was found to be in good agreement with the observed activation enthalpy for methyl acrylate and cyclopentadiene, however, this method does not predict the stereoselectivities correctly in all cases. The hydrogen bonding between water and polarized transition states seems to be important for rate acceleration in wate

4-Substituted norsnoutanones: a new probe system forevaluatingelectronic effects in π -facial selectivity in nucleophilicadditions

Remotely substituted norsnoutanone derivatives show significant and consistent π-face selectivity in nucleophilic additions, revealing the interplay of orbital and electrostatic effects

π-Facial Selectivity in Diels-Alder Cycloadditions

Diels-Alder reactions between π-facially differentiated dienes and/or π-facially differentiated dienophiles frequently proceed with remark-able π-facial selectivity. Experimental and theoretical studies have been undertaken in an effort to gain insight into the fundamental origins of this phenomenon. Reactions of interest in this connection include thermal [4 + 2] cycloadditions between (i) various dienophiles and cage-annulated 1,3-cyclohexadienes (i.e. systems 1, 4, 6, and 9) and (ii) various dienes and cage-annulated dienophiles (i.e. systems 1a, 11a, and 14). The results of relevant molecular mechanics, semiempirical, and ab initio molecular orbital calculations generally are consistent with experiment

Probing the Structural and Electronic Effects on the Origin of π‑Facial Stereoselectivity in 1‑Methylphosphole 1‑Oxide Cycloadditions and Cyclodimerization

We have examined the π-facial stereoselectivity in the Diels–Alder reactions of phosphole oxides computationally. The experimentally observed syn-cycloadditions have been rationalized with the Cieplak model and distortion–interaction model. The natural bond orbital analysis suggests that the hyperconjugative interactions are energetically preferred between the antiperiplanar methyl group present in the −PO unit and the developing incipient (−C–C−) bond in syn-adducts in accordance with the Cieplak model. The distortion–interaction analysis carried out for syn and anti transition states of Diels–Alder reactions of 1-substituted phosphole 1-oxide with different dienophiles reveals that the syn selectivity is favored by distortions and interaction energies compared with the anti selectivity. The formation of a syn adduct is also stabilized by the πCC–σ*PO orbital interaction, and the repulsive n−π interaction destabilizes the anti adduct that leads to the 7.0 kcal/mol thermodynamic preference for the former adduct. Furthermore, the distortion–interaction model rationalizes the formation of stereospecific products in these Diels–Alder reactions, which however is not explicable with the much-debated Cieplak model

An experimental and computational analysis on the differential role of the positional isomers of symmetric bis-2-(pyridyl)-1H-benzimidazoles as DNA binding agents

Three symmetrical positional isomers of bis-2-(n-pyridyl)-1H-benzimidazoles (n = 2, 3, 4) were synthesized and DNA binding studies were performed with these isomeric derivatives. Like bisbenzimidazole compound Hoechst 33258, these molecules also demonstrate AT-specific DNA binding. The binding affinities of 3-pyridine (m-pyben) and 4-pyridine (p-pyben) derivatized bisbenzimidazoles to double-stranded DNA were significantly higher compared to 2-pyridine derivatized benzimidazole o-pyben. This has been established by combined experimental results of isothermal fluorescence titration, circular dichroism, and thermal denaturation of DNA. To rationalize the origin of their differential binding characteristics with double-stranded DNA, computational structural analyses of the uncomplexed ligands were performed using ab initio/Density Functional Theory. The molecular conformations of the symmetric head-to-head bisbenzimidazoles have been computed. The existence of intramolecular hydrogen bonding was established in o-pyben, which confers a conformational rigidity to the molecule about the bond connecting the pyridine and benzimidazole units. This might cause reduction in its binding affinity to double-stranded DNA compared to its para and meta counterparts. Additionally, the predicted stable conformations for p-, m-, and o-pyben at the B3LYP/6-31G∗ and RHF/6-31G∗ levels were further supported by experimental pKa determination. The results provide important information on the molecular recognition process of such symmetric head to head bisbenzimidazoles toward duplex DNA

DFT Study To Explore the Importance of Ring Size and Effect of Solvents on the Keto–Enol Tautomerization Process of α- and β‑Cyclodiones

We have explored the effect of ring size on keto–enol tautomerization of α- and β-cyclodiones using the M062X-SMD_aq/6-31+G­(d,p)//M062X/6-31+G­(d,p) level of theory. The calculated results show that the activation free energy barrier for the keto–enol tautomerization process of α-cyclopropanedione (<b>1</b>) is 54.9 kcal/mol, which is lower compared to that of the other cyclic diketo systems studied here. The four-membered α- and β-cyclobutanedione (<b>2</b> and <b>6</b>) do not favor keto–enol tautomerization unlike other studied cyclic systems because of the ring strain developed in the transition-state geometries and their corresponding products. Water-assisted keto–enol tautomerization with one molecule reveals that the free energy activation barriers reduce almost half compared to those for the uncatalyzed systems. The two-water-assisted process is favorable as the activation free energy barriers lowered by ∼10 kcal/mol compared to those of the one-water-assisted process. The ion-pair formation seems to govern the lowering of activation barriers of α- and β-cyclodiones with two water molecules during the keto–enol tautomerization process, which however also overcomes the favorable aromatization in the three-membered ring system. The free energy activation barriers calculated with the M062X-SMD_aq/6-31+G­(d,p) level predicted that the keto–enol tautomerization process for the α-cyclodiones follows the following trend: <b>2</b> > <b>3</b> > <b>4</b> > <b>5</b> > <b>1</b>. Water-assisted tautomerization of α-cyclodiones also predicted <b>1-W</b> and <b>1-2W</b> as the most favored processes; however, <b>5-W</b> and <b>5-2W</b> were found to be disfavored in this case. The β-cyclodione systems also showed similar trends as obtained with α-diketone systems. The influence of bulk solvent on the keto–enol tautomerization process favors the formation of the enol form in a more polar solvent medium even under mixed solvent conditions in acetonitrile and hexane at M062X-SMD_acetonitrile/6-31+G­(d,p) and M062X-SMD_hexane/6-31+G­(d,p) levels of theory