Conformational Energy Research Articles

NMR Provides Unique Insight into the Functional Dynamics and Interactions of Intrinsically Disordered Proteins.

Intrinsically disordered proteins are ubiquitous throughout all known proteomes, playing essential roles in all aspects of cellular and extracellular biochemistry. To understand their function, it is necessary to determine their structural and dynamic behavior and to describe the physical chemistry of their interaction trajectories. Nuclear magnetic resonance is perfectly adapted to this task, providing ensemble averaged structural and dynamic parameters that report on each assigned resonance in the molecule, unveiling otherwise inaccessible insight into the reaction kinetics and thermodynamics that are essential for function. In this review, we describe recent applications of NMR-based approaches to understanding the conformational energy landscape, the nature and time scales of local and long-range dynamics and how they depend on the environment, even in the cell. Finally, we illustrate the ability of NMR to uncover the mechanistic basis of functional disordered molecular assemblies that are important for human health.

PNC-27, a Chimeric p53-Penetratin Peptide Binds to HDM-2 in a p53 Peptide-like Structure, Induces Selective Membrane-Pore Formation and Leads to Cancer Cell Lysis.

PNC-27, a 32-residue peptide that contains an HDM-2 binding domain and a cell-penetrating peptide (CPP) leader sequence kills cancer, but not normal, cells by binding to HDM-2 associated with the plasma membrane and induces the formation of pores causing tumor cell lysis and necrosis. Conformational energy calculations on the structure of PNC-27 bound to HDM-2 suggest that 1:1 complexes form between PNC-27 and HDM-2 with the leader sequence pointing away from the complex. Immuno-scanning electron microscopy was carried out with cancer cells treated with PNC-27 and decorated with an anti-PNC-27 antibody coupled to 6 nm gold particles and an anti-HDM-2 antibody linked to 15 nm gold particles. We found multiple 6 nm- and 15 nm-labeled gold particles in approximately 1:1 ratios in layered ring-shaped structures in the pores near the cell surface suggesting that these complexes are important to the pore structure. No pores formed in the control, PNC-27-treated untransformed fibroblasts. Based on the theoretical and immuno-EM studies, we propose that the pores are lined by PNC-27 bound to HDM-2 at the membrane surface with the PNC-27 leader sequence lining the pores or by PNC-27 bound to HDM-2.

Controlling Solution-State Aggregation and Solid-State Microstructures of Conjugated Polymers by Tuning Backbone Conformation.

Molecular ordering of conjugated polymers both in solution-state aggregates and in solid-state microstructures is a determining factor of the charge transport properties in optoelectronic devices. However, the effect of backbone conformation in conjugated polymers on assembly structures is still unclear. Herein, to understand such backbone conformation effect, three novel chlorinated benzodifurandionge-based oligo(p-phenylene vinylene) (BDOPV) polymers are systematically developed. These BDOPV-based polymers exhibit significantly twisted backbone conformation (near 90° interunit torsion angle) between conjugated units, which can prevent polymer chains from forming ordered assembly structures by increasing conformational energy penalty in closely packed chains. A higher rotational barrier of the torsion angle would further prevent polymer chains from assembling, finally resulting in nonaggregated chains in solution and highly disordered solid-state packing structures. This work will deepen the understanding of the relationship between polymer backbone conformation and assembly structures, contributing to the exploration of the structure-property relationship of polymers.

Small-Basis Set Density-Functional Theory Methods Corrected with Atom-Centered Potentials.

Density functional theory (DFT) is currently the most popular method for modeling noncovalent interactions and thermochemistry. The accurate calculation of noncovalent interaction energies, reaction energies, and barrier heights requires choosing an appropriate functional and, typically, a relatively large basis set. Deficiencies of the density-functional approximation and the use of a limited basis set are the leading sources of error in the calculation of noncovalent and thermochemical properties in molecular systems. In this article, we present three new DFT methods based on the BLYP, M06-2X, and CAM-B3LYP functionals in combination with the 6-31G* basis set and corrected with atom-centered potentials (ACPs). ACPs are one-electron potentials that have the same form as effective-core potentials, except they do not replace any electrons. The ACPs developed in this work are used to generate energy corrections to the underlying DFT/basis-set method such that the errors in predicted chemical properties are minimized while maintaining the low computational cost of the parent methods. ACPs were developed for the elements H, B, C, N, O, F, Si, P, S, and Cl. The ACP parameters were determined using an extensive training set of 118655 data points, mostly of complete basis set coupled-cluster level quality. The target molecular properties for the ACP-corrected methods include noncovalent interaction energies, molecular conformational energies, reaction energies, barrier heights, and bond separation energies. The ACPs were tested first on the training set and then on a validation set of 42567 additional data points. We show that the ACP-corrected methods can predict the target molecular properties with accuracy close to complete basis set wavefunction theory methods, but at a computational cost of double-ζ DFT methods. This makes the new BLYP/6-31G*-ACP, M06-2X/6-31G*-ACP, and CAM-B3LYP/6-31G*-ACP methods uniquely suited to the calculation of noncovalent, thermochemical, and kinetic properties in large molecular systems.

Theoretical study of the helical conformers and ECD spectra of 8-aminoquinoline polymers

In this study, the helical conformers and absorption spectra of three types of 8-aminoquinoline oligoamides were studied. The stable conformers of these oligoamides connected with chiral β-pinene at their terminals were searched, and their dominant conformers and corresponding Boltzmann statistical weights were obtained. The excitation energy and oscillator strength of the dominant conformers were calculated, and the UV and electronic circular dichroism (ECD) spectra were also simulated. β-pinene can form delocalized π-bonds at the C-terminal, which results in a strong R band for CQn. Furthermore, the degree of polymerization also affected the strength of the absorption band for all the oligoamides.

Fast and Accurate Quantum Mechanical Modeling of Large Molecular Systems Using Small Basis Set Hartree-Fock Methods Corrected with Atom-Centered Potentials.

There has been significant interest in developing fast and accurate quantum mechanical methods for modeling large molecular systems. In this work, by utilizing a machine learning regression technique, we have developed new low-cost quantum mechanical approaches to model large molecular systems. The developed approaches rely on using one-electron Gaussian-type functions called atom-centered potentials (ACPs) to correct for the basis set incompleteness and the lack of correlation effects in the underlying minimal or small basis set Hartree-Fock (HF) methods. In particular, ACPs are proposed for ten elements common in organic and bioorganic chemistry (H, B, C, N, O, F, Si, P, S, and Cl) and four different base methods: two minimal basis sets (MINIs and MINIX) plus a double-ζ basis set (6-31G*) in combination with dispersion-corrected HF (HF-D3/MINIs, HF-D3/MINIX, HF-D3/6-31G*) and the HF-3c method. The new ACPs are trained on a very large set (73 832 data points) of noncovalent properties (interaction and conformational energies) and validated additionally on a set of 32 048 data points. All reference data are of complete basis set coupled-cluster quality, mostly CCSD(T)/CBS. The proposed ACP-corrected methods are shown to give errors in the tenths of a kcal/mol range for noncovalent interaction energies and up to 2 kcal/mol for molecular conformational energies. More importantly, the average errors are similar in the training and validation sets, confirming the robustness and applicability of these methods outside the boundaries of the training set. In addition, the performance of the new ACP-corrected methods is similar to complete basis set density functional theory (DFT) but at a cost that is orders of magnitude lower, and the proposed ACPs can be used in any computational chemistry program that supports effective-core potentials without modification. It is also shown that ACPs improve the description of covalent and noncovalent bond geometries of the underlying methods and that the improvement brought about by the application of the ACPs is directly related to the number of atoms to which they are applied, allowing the treatment of systems containing some atoms for which ACPs are not available. Overall, the ACP-corrected methods proposed in this work constitute an alternative accurate, economical, and reliable quantum mechanical approach to describe the geometries, interaction energies, and conformational energies of systems with hundreds to thousands of atoms.

Transferable Neural Network Potential Energy Surfaces for Closed-Shell Organic Molecules: Extension to Ions.

Transferable high dimensional neural network potentials (HDNNPs) have shown great promise as an avenue to increase the accuracy and domain of applicability of existing atomistic force fields for organic systems relevant to life science. We have previously reported such a potential (Schrödinger-ANI) that has broad coverage of druglike molecules. We extend that work here to cover ionic and zwitterionic druglike molecules expected to be relevant to drug discovery research activities. We report a novel HDNNP architecture, which we call QRNN, that predicts atomic charges and uses these charges as descriptors in an energy model that delivers conformational energies within chemical accuracy when measured against the reference theory it is trained to. Further, we find that delta learning based on a semiempirical level of theory approximately halves the errors. We test the models on torsion energy profiles, relative conformational energies, geometric parameters, and relative tautomer errors.

The interplay of intra- and intermolecular errors in modeling conformational polymorphs.

Conformational polymorphs of organic molecular crystals represent a challenging test for quantum chemistry because they require careful balancing of the intra- and intermolecular interactions. This study examines 54 molecular conformations from 20 sets of conformational polymorphs, along with the relative lattice energies and 173 dimer interactions taken from six of the polymorph sets. These systems are studied with a variety of van der Waals-inclusive density functionals theory models; dispersion-corrected spin-component-scaled second-order Møller-Plesset perturbation theory (SCS-MP2D); and domain local pair natural orbital coupled cluster singles, doubles, and perturbative triples [DLPNO-CCSD(T)]. We investigate how delocalization error in conventional density functionals impacts monomer conformational energies, systematic errors in the intermolecular interactions, and the nature of error cancellation that occurs in the overall crystal. The density functionals B86bPBE-XDM, PBE-D4, PBE-MBD, PBE0-D4, and PBE0-MBD are found to exhibit sizable one-body and two-body errors vs DLPNO-CCSD(T) benchmarks, and the level of success in predicting the relative polymorph energies relies heavily on error cancellation between different types of intermolecular interactions or between intra- and intermolecular interactions. The SCS-MP2D and, to a lesser extent, ωB97M-V models exhibit smaller errors and rely less on error cancellation. Implications for crystal structure prediction of flexible compounds are discussed. Finally, the one-body and two-body DLPNO-CCSD(T) energies taken from these conformational polymorphs establish the CP1b and CP2b benchmark datasets that could be useful for testing quantum chemistry models in challenging real-world systems with complex interplay between intra- and intermolecular interactions, a number of which are significantly impacted by delocalization error.

Conformer-Specific Spectroscopy and IR-Induced Isomerization of a Model γ-Peptide: Ac-γ4-Phe-NHMe.

Single-conformation IR and UV spectroscopy of the prototypical capped γ-peptide Ac-γ4-Phe-NHMe (γ4F) was carried out under jet-cooled conditions in the gas phase in order to understand its innate conformational preferences in the absence of a solvent. We obtained conformer-specific IR and UV spectra and compared the results with calculations to make assignments and explore the differences between the γ2- and γ4-substituted molecules. We found four conformers of γ4F in our experiment. Three conformers form nine-membered hydrogen-bonded rings (C9) enclosed by an NH···O═C H-bond but differing in their phenyl ring positions (a, g+, and g-). The fourth conformer forms a strained seven-membered hydrogen-bonded ring in which the amide groups lie in a nominally anti-parallel arrangement stacked on top of one another (labeled S7). This conformer is a close analogue of the amide-stacked conformer (S) found previously in γ2F, in which the Phe side chain is substituted at the γ2 position, Ac-γ2-Phe-NHMe (J. Am. Chem. Soc. 2009, 131, 14243-14245). IR population transfer spectroscopy was used to determine the fractional abundances of the γ4F conformers in the expansion. A combination of force field and density functional theory calculations is used to map out the conformational potential energy surfaces for γ4F and compare it with its γ2F counterpart. Based on this analysis, the phenyl ring prefers to take up structures that facilitate NH···π interactions in γ4F or avoid phenyl interactions with the C═O group in γ2F. The disconnectivity graph for γ4F reveals separate basins associated with the C9 and amide-stacked conformational families, which are separated by a barrier of about 42 kJ/mol. The overall shape of the potential energy surface bears a resemblance to peptides and proteins that have a misfolding pathway that competes with the formation of the native structure.

Dynamic organic mechanoluminescence (ML): The roles of Mechano-induced conformational isomer and energy transfer from ML to photoluminescence (PL)

Organic mechanoluminescence (ML), especially dynamic ML with color change along continuously grinding, is promising for mechano-dependent applications of lighting, imaging and sensors. Here, new insights for fine tuning ML feature from no, stable to dynamic characteristic, are reported by simply changing the substituted position of bromine atom on isomers of phenothiazine (PTZ) derivative (Br-BPZ). Additionally, three key factors, including mechano-induced conformation transformation, mixture formation of crystal and amorphous powders after ground as well as the energy transfer from ML of crystal part to photoluminescence (PL) of amorphous part inside, have been experimentally confirmed for promoting dynamic ML (an extremely rare kind of ML) of organic materials. These findings not only provide a strategy for design of organic ML but also develop a new application of colorful ML display without doping based on dynamic ML materials.

Structural Stability Analysis of Proteins Using End-to-End Distance: A 3D-RISM Approach

The stability of a protein is determined from its properties and surrounding solvent. In our previous study, the total energy as a sum of the conformational and solvation free energies was demonstrated to be an appropriate energy function for evaluating the stability of a protein in a protein folding system. We plotted the various energies against the root mean square deviation, required as a reference structure. Herein, we replotted the various energies against the end-to-end distance between the N- and C-termini, which is not a required reference and is experimentally measurable. The solvation free energies for all proteins tend to be low as the end-to-end distance increases, whereas the conformational energies tend to be low as the end-to-end distance decreases. The end-to-end distance is one of interesting measures to study the behavior of proteins.

New Hypercoordinating Organostannanes for the Modular Functionalization of Mono‐ and Polystannanes: Synthetic and Computational Studies**

AbstractA series of potentially hypercoordinate tin compounds derived from a substitutionally labile tosyl stannane (5) was produced to gain access to a library of propyloxybiphenyl (11), propylmethoxy (12, 14, 18, 22) or propylthioester (13, 15, 19, 23) stannanes for structure/property/polymerization investigations. Structural characterizations by single crystal X‐ray diffraction of 12, 14, 18 and 19 were also undertaken. The relative energies of hypercoordinate conformers for the propylmethoxystannanes 12, 14, 18, and 22 were determined with DFT methods and the fractional abundance of conformers in the gas and solution (CHCl3) phase were estimated. Relativistic DFT calculations of 119Sn NMR chemical shifts were carried out for a series of non‐hypercoordinate reference compounds and the conformers, allowing the estimation of Boltzmann‐averaged chemical shifts of the hypercoordinate propylmethoxystannanes. A semi‐crystalline homopolymer (25) was isolated from the dehydropolymerization of 22 using Wilkinson's catalyst. Conversion of the liable tosylated polystannane (24) to a new partially substituted polystannane (28) via nucleophile displacement reactions was achieved.

Simultaneous parametrization of torsional and third-neighbor interaction terms in force-field development: The LLS-SC algorithm.

The calibration of torsional interaction terms by fitting relative gas-phase conformational energies against their quantum-mechanical values is a common procedure in force-field development. However, much less attention has been paid to the optimization of third-neighbor nonbonded interaction parameters, despite their strong coupling with the torsions. This article introduces an algorithm termed LLS-SC, aimed at simultaneously parametrizing torsional and third-neighbor interaction terms based on relative conformational energies. It relies on a self-consistent (SC) procedure where each iteration involves a linear least-squares (LLS) regression followed by a geometry optimization of the reference structures. As a proof-of-principle, this method is applied to obtain torsional and third-neighbor interaction parameters for aliphatic chains in the context of the GROMOS 53A6 united-atom force field. The optimized parameter set is compared to the original one, which has been fitted manually against thermodynamic properties for small linear alkanes. The LLS-SC implementation is freely available under http://github.com/mssm-labmmol/profiler.

From Protein Design to the Energy Landscape of a Cold Unfolding Protein.

Understanding protein folding is crucial for protein sciences. The conformational spaces and energy landscapes of cold (unfolded) protein states, as well as the associated transitions, are hardly explored. Furthermore, it is not known how structure relates to the cooperativity of cold transitions, if cold and heat unfolded states are thermodynamically similar, and if cold states play important roles for protein function. We created the cold unfolding 4-helix bundle DCUB1 with a de novo designed bipartite hydrophilic/hydrophobic core featuring a hydrogen bond network which extends across the bundle in order to study the relative importance of hydrophobic versus hydrophilic protein–water interactions for cold unfolding. Structural and thermodynamic characterization resulted in the discovery of a complex energy landscape for cold transitions, while the heat unfolded state is a random coil. Below ∼0 °C, the core of DCUB1 disintegrates in a largely cooperative manner, while a near-native helical content is retained. The resulting cold core-unfolded state is compact and features extensive internal dynamics. Below −5 °C, two additional cold transitions are seen, that is, (i) the formation of a water-mediated, compact, and highly dynamic dimer, and (ii) the onset of cold helix unfolding decoupled from cold core unfolding. Our results suggest that cold unfolding is initiated by the intrusion of water into the hydrophilic core network and that cooperativity can be tuned by varying the number of core hydrogen bond networks. Protein design has proven to be invaluable to explore the energy landscapes of cold states and to robustly test related theories.

Analyses of experiment based ramachandran plots of tri-, tetra- and pentapeptides reveal residue dependent interactions between neighbors

Flory's canonical random coil model is based on the assumption that conformational fluctuations of amino acid residues in unfolded poly(oligo)peptides and proteins are uncorrelated (isolated pair hypothesis, IPH). It implies that conformational energies, entropies, and solvation free energies are all additive. Nearly 25 years ago, analyses of coil libraries casted some doubt on this notion in that they revealed that aromatic residues could change the 3J(HNHCα) coupling of their neighbors. Since then multiple lines of bioinformatical, computational and lately also experimental evidence indicate that the conformational propensities of amino acids in unfolded peptides and proteins depend on their nearest neighbors and possibly even on the nature of the second neighbor.

Association mechanism of remimazolam-serum albumin nano-drug for potential clinical application

Bovine serum albumin (BSA) was selected to act as a stabilizer for the growth of remimazolam-BSA particles using thermal denaturation precipitation. The remimazolam-BSA NPs showed a sphere shape, with a ζ-potential of −11.3 mV and an average diameter of 84.3 nm under electron microscopy. The drug release study of remimazolam in vitro showed a sustained and controlled release pattern. The common ways of spectroscopy like circular dichroism (CD), UV–vis, and steady-state fluorescence were all used to investigate the physicochemical association properties. A moderate binding affinity between BSA and remimazolam with a stoichiometry of 1:1 was revealed by fluorescence results (binding constant: 1.87 × 104 M−1 at body temperature). The participation of hydrophobic forces in the formation of the complex has been confirmed by analyzing the thermodynamic results of the binding data (ΔS○ = 110 J mol-1 K-1 and ΔH○ = 8.63 × 103 J mol-1). The prior remimazolam binding site is located in site II of BSA with slight protein conformational changes and probable energy transfer.

Characterizing the rugged conformational energy landscape of RNA

RNA plays crucial roles in almost all essential biological functions. To perform these functions, RNA must fold into complex three-dimensional structures and often undergo functionally important structural rearrangements. Perhaps the most fundamental and commonly found RNA structural elements are RNA stem-loops, which often nucleate the folding of larger, more complex structural motifs; serve as recognition sites for RNA binding proteins; and are components of conformational switches that regulate RNA function.

Quantum mechanical and molecular dynamics simulations of retinal systems utilizing novel artificial-intelligence-derived force fields

G-protein-coupled receptors (GPCRs) are a superfamily of transmembrane proteins that perform diverse signaling roles in organisms, including humans. This makes them an attractive target for pharmaceuticals, with 134 different GPCRs being currently targeted by roughly 700 drugs. Here we studied the retinylidene cofactor of GPCR rhodopsin that is responsible for initiating phototransduction in many organisms. The conformational energy landscape of this retinylidene is both complex and critical for the activation of the rhodopsin protein, which depends not only on specific isomers but on rotamers as well.

Synthetic, spectroscopic, and computational investigations of readily accessible 2‐phenyl‐3‐alkylbenzoxazaboroles

AbstractWe report several new benzoxazaboroles using 2‐aminophenol or 2‐(alkylamino)phenols and phenylboronic acid derivatives. Bis(benzoxazaborole)s were also synthesized using aminophenols and diboronic acids. Characterization of benzoxazaboroles and bis(benzoxazaborole)s was carried out using 1H NMR, 13C NMR, UV–visible, and fluorescence spectroscopic methods along with mass spectrometry and X‐ray crystallography for structural identification. Computational calculations of benzoxazaboroles and bis(benzoxazaborole)s were utilized to support and add to the experimental results. This includes calculations of conformational energies, bond lengths, HOMO‐LUMO energies, and electrostatic potential maps.

Comparison of green bio-based cerium/alginate vs. copper/alginate beads: a study of vibrational and thermal properties using experimental and theoretical methods.

Herein, bio-based alginates (Alg) containing metallic beads (Ce and Cu) were synthesized via an alginate cross-linking method, and their properties were studied using experimental techniques combined with theoretical simulations. Materials were characterized through Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and scanning electron microscope (SEM) images, to determine the cross-linking structural features, thermal stability, and surface morphology of alginates. Besides, density functional theory (DFT) methods were employed to calculate global reactivity parameters such as HOMO-LUMO gap energies (ΔEH-L), electronegativity (χ), hardness (η), and electrophilic and nucleophilic indicators, using both gas and aqueous media for the study of the complexation process. Among other features, characterization of the thermal properties showed that Alg@Ce and Alg@Cu alginate beads behave differently as a function of the temperature. This behavior was also predicted by the conformation energy differences between Alg@Ce and Alg@Cu, which were found out theoretically and explained with the combined study of the vibrational modes between the carboxylate group with either Ce or Cu. Overall, the reactivity of the Alg@Ce alginate bead was higher than that of the Alg@Cu counterpart, results could be used as a cornerstone to employed the materials here studied in a wide range of applications.