Conformational Energy Research Articles

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.

Optimizing Lennard-Jones parameters by coupling single molecule and ensemble target data

This contribution is a proof-of-concept that a diverse set of training observables leads to a meaningful force field even if a very limited number of thermodynamic state points (i.e. temperatures) is used. This approach generates optimized force-field parameters, enabling the user to extract additional information from MD simulations. The ultimate goal is to extend this approach and enable an increased amount of observables to be reproduced using a single force field for a series of chemically similar molecules (e.g. oligomer hydrocarbons). Specifically, we present a new optimization strategy to expand the limits of existing force fields and investigate how much added error is introduced to already reproducible observables. For this purpose, we optimized the Lennard-Jones parameters of n-octane using an isolated molecule's relative conformational energies and the liquid-phase density (293.15 K) for a molecular ensemble as optimization objectives. To test the impact on other observables, additional substances and temperatures that were not part of the training set were evaluated. This evaluation includes the surface tension, viscosity and density for n-hexane, n-heptane, n-octane and n-nonane at 293.15, 315.15 and 338.15 K. We show that it is possible to expand the limits of a force field, improving its overall accuracy at a small cost to its previously well-reproduced observables. Additionally, we propose approaches for further developments of the optimization strategy to increase the observables accuracies that suffer a loss in exchange for the capability of reproducing additional properties.

Decoding the Host-Parasite Protein Interactions Involved in Cerebral Malaria Through Glares of Molecular Dynamics Simulations.

Malaria causes millions of deaths every year. The malaria parasite spends a substantial part of its life cycle inside human erythrocytes. Inside erythrocytes, it synthesizes and displays various proteins onto the erythrocyte surface, such as Plasmodium falciparum erythrocytic membrane protein-1 (PfEMP1). This protein contains cysteine-rich interdomain region (CIDR) domains which have many subtypes based on sequence diversity and can cross-talk with host molecules. The CIDRα1.4 subtype can attach host endothelial protein C receptor (EPCR). This interaction facilitates infected erythrocyte adherence to brain endothelium and subsequent development of cerebral malaria. Through molecular dynamics simulations in conjunction with the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) method, we explored the mechanism of interaction in the CIDRα1-EPCR complex. We examined the structural behavior of two CIDRα1 molecules (encoded by HB3-isolate var03-gene and IT4-isolate var07-gene) with EPCR unbound and bound (complex) forms. HB3var03CIDRα1 in apo and complexed with EPCR was comparatively more stable than IT4var07CIDRα1. Both of the complexes adopted two distinct conformational energy states. The hydrophobic residues played a crucial role in the binding of both complexes. For HB3var03CIDRα1-EPCR, the dominant energetic components were total polar interactions, while in IT4var07CIDRα1-EPCR, the primary interaction was van der Waals and nonpolar solvation energy. The study also revealed details such as correlated conformational motions and secondary structure evolution. Further, it elucidated various hotspot residues involved in protein-protein recognition. Overall, our study provides additional information on the structural behavior of CIDR molecules in unbound and receptor-bound states, which will help to design potent inhibitors.

16OSTM10: a new open-shell transition metal conformational energy database to challenge contemporary semiempirical and force field methods.

A new database, 16OSTM10, containing 10 conformations for each of 16 non-multireference realistic-size open-shell transition metal (OSTM) complexes has been developed. Contemporary composite density functional theory (DFT) (PBEh-3c and B97-3c), semiempirical (PM6 and PM7) and the GFNn-xTB/FF family methods were examined against conventional DFT (PBE-D3(BJ), PBE0-D3(BJ), M06 and ωB97X-V) to reproduce the conformational energies. While good performance is observed for the conventional (the average Pearson correlation coefficient is ρ = 0.91) and composite DFT (average ρ = 0.93), semiempirical and force-field methods should still be used with caution for these challenging compounds. The corresponding average ρ values are 0.53 (PM6 and PM7), 0.75 (GFN1-xTB and GFN2-xTB) and 0.62 (GFN-FF). Accounting for the intramolecular dispersion interactions turned out to be crucial for 4 OSTM complexes bearing bulky substituents in close proximity to each other. The influence of the scalar relativistic effects on the conformational energies is negligible for the considered 3d metal species.

Conformational preferences in a series of α-hydroxy ketone derivatives: interplay of conformational energies and lattice cohesive energies

A detailed structural analysis of a series of α-hydroxy ketone derivatives in terms of lattice energies and conformational energies reveals the competing factors of inter- and intramolecular interactions that direct conformational preferences.

Catching the Conformational Wave: Measuring the Working Strokes of Protofilaments as They Curl Outward from Disassembling Microtubule Tips.

Optical traps have enabled foundational studies of how mechanoenzymes such as kinesins and dynein motors walk along microtubules, how myosins move along F-actin, and how nucleic acid enzymes move along DNA or RNA. Often the filamentous substrates serve merely as passive tracks for mechanoenzymes but microtubules and F-actin are themselves dynamic protein polymers, capable of generating movement and force independently of conventional motors. Microtubule-driven forces are particularly important during mitosis, when they align duplicated chromosomes at the metaphase plate and then pull them apart during anaphase. These vital movements depend on specialized protein assemblies called kinetochores that couple the chromosomes to the tips of dynamic microtubule filaments, thereby allowing filament shortening to produce pulling forces. Although great strides have been made toward understanding the structures and functions of many kinetochore subcomplexes, the biophysical basis for their coupling to microtubule tips remains unclear. During tip disassembly, strain energy is released when straight protofilaments in the microtubule lattice curl outward, creating a conformational wave that propagates down the microtubule. A popular viewpoint is that the protofilaments as they curl outward hook elements of the kinetochore and tug on them, transferring some of their curvature strain energy to the kinetochore. As a first step toward testing this idea, we recently developed a laser trap assay to directly measure the working strokes generated by curling protofilaments. Our "wave" assay is based on an earlier pioneering study, with improvements that allow measurement of curl-driven movements as functions of force and quantification of their conformational strain energy. In this chapter, we provide a detailed protocol for our assay and describe briefly our instrument setup and data analysis methods.

Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs.

G protein-coupled receptors (GPCRs) make up the largest superfamily of integral membrane proteins and play critical signal transduction roles in many physiological processes. Developments in molecular biology, biophysical, biochemical, pharmacological, and computational techniques aimed at these important therapeutic targets are beginning to provide unprecedented details on the structural as well as functional basis of their pleiotropic signaling mediated by G proteins, β arrestins, and other transducers. This pleiotropy presents a pharmacological challenge as the same ligand-receptor interaction can cause a therapeutic effect as well as an undesirable on-target side-effect through different downstream pathways. GPCRs don't function as simple binary on-off switches but as finely tuned shape-shifting machines described by conformational ensembles, where unique subsets of conformations may be responsible for specific signaling cascades. X-ray crystallography and more recently cryo-electron microscopy are providing snapshots of some of these functionally-important receptor conformations bound to ligands and/or transducers, which are being utilized by computational methods to describe the dynamic conformational energy landscape of GPCRs. In this chapter, we review the progress in computational conformational sampling methods based on molecular dynamics and discrete sampling approaches that have been successful in complementing biophysical and biochemical studies on these receptors in terms of their activation mechanisms, allosteric effects, actions of biased ligands, and effects of pathological mutations. Some of the sampled simulation time scales are beginning to approach receptor activation time scales. The list of conformational sampling methods and example uses discussed is not exhaustive but includes representative examples that have pushed the limits of classical molecular dynamics and discrete sampling methods to describe the activation energy landscape of GPCRs.

DFT/TD-DFT ANALYSIS OF 2-CHLORO-7-METHYLQUINOLINE-3-CARBALDEHYDE USING COMPUTER COMPUTING METHOD

Quinolines are the essence of many natural products, drugs and were found in synthetic compounds. Quinoline derivatives containing a quinoline ring are used in a variety of biological and pharmaceutical activities, e.g. anticancer, antibacterial, antifungal, antiplasmodial, antihistamine, antimalarial and antituberculosis. In this study, 2-Chloro-7-Methylquinoline-3-Carbaldehyde (ClMQC) molecule, which is a quinoline derivative, was selected and analyzed. The stable structures of ClMQC molecule with minimum energy were investigated by density functional theory (DFT) together with B3LYP/6-311++G(d,p) method. It was seen that there are two different conformers (trans and cis) with minimum energy in the scanning made depending on the C─C─C=O dihedral angle. As a result of the calculation with the B3LYP/6-311++G(d,p) level, the energy difference (E+ZPV) between the two conformers was calculated as 14.60 kJ mol-1. Oscillator strength and excitation energies were analyzed by calculating the time-dependent DFT (TD-DFT). The energy differences between the excited energy levels are given in the graph. This was done by adding the ground state energies of both conformers. The energy corresponding to HOMO-LUMO was calculated to correspond to the S0→S2 transition for both conformers. The excitation energy values were calculated as 3.75 and 3.84 eV for trans and cis, respectively.

Fragment-Based Quantum Mechanical Calculation of Excited-State Properties of Fluorescent RNAs.

Fluorescent RNA aptamers have been successfully applied to track and tag RNA in a biological system. However, it is still challenging to predict the excited-state properties of the RNA aptamer–fluorophore complex with the traditional electronic structure methods due to expensive computational costs. In this study, an accurate and efficient fragmentation quantum mechanical (QM) approach of the electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) scheme was applied for calculations of excited-state properties of the RNA aptamer–fluorophore complex. In this method, the excited-state properties were first calculated with one-body fragment quantum mechanics/molecular mechanics (QM/MM) calculation (the excited-state properties of the fluorophore) and then corrected with a series of two-body fragment QM calculations for accounting for the QM effects from the RNA on the excited-state properties of the fluorophore. The performance of the EE-GMFCC on prediction of the absolute excitation energies, the corresponding transition electric dipole moment (TEDM), and atomic forces at both the TD-HF and TD-DFT levels was tested using the Mango-II RNA aptamer system as a model system. The results demonstrate that the calculated excited-state properties by EE-GMFCC are in excellent agreement with the traditional full-system time-dependent ab initio calculations. Moreover, the EE-GMFCC method is capable of providing an accurate prediction of the relative conformational excited-state energies for different configurations of the Mango-II RNA aptamer system extracted from the molecular dynamics (MD) simulations. The fragmentation method further provides a straightforward approach to decompose the excitation energy contribution per ribonucleotide around the fluorophore and then reveals the influence of the local chemical environment on the fluorophore. The applications of EE-GMFCC in calculations of excitation energies for other RNA aptamer–fluorophore complexes demonstrate that the EE-GMFCC method is a general approach for accurate and efficient calculations of excited-state properties of fluorescent RNAs.

Quantum Chemical Calculation and Evaluation of Partition Coefficients for Classical and Emerging Environmentally Relevant Organic Compounds.

Octanol/water (KOW), octanol/air (KOA), and hexadecane/air (KHdA) partition coefficients are calculated for 67 organic compounds of environmental concern using computational chemistry. The extended CRENSO workflow applied here includes the calculation of extensive conformer ensembles with semiempirical methods and refinement through density functional theory, taking into account solvation models, especially COSMO-RS, and thermostatistical contributions. This approach is particularly advantageous for describing large and nonrigid molecules. With regard to KOW and KHdA, one can refer to many experimental data from direct and indirect measurement methods, and very good matches with results from our quantum chemical workflow are evident. In the case of the KOA values, however, good matches are only obtained for the experimentally determined values. Larger systematic deviations between data computed here and available, nonexperimental quantitative structure-activity relationship literature data occur in particular for phthalic acid esters and organophosphate esters. From a critical analysis of the coefficients calculated in this work and comparison with available literature data, we conclude that the presented quantum chemical composite approach is the most powerful so far for calculating reliable partition coefficients because all physical contributions to the conformational free energy are considered and the structure ensembles for the two phases are generated independently and consistently.

Spatial-thermodynamic understanding of stabilization mechanism using computational approaches and molecular-level elucidation of the mechanism of crystal transformation in polymorphic irbesartan nanosuspensions

Irbesartan polymorphisms possess low solubility properties, nanosuspensions represent a method for improving the dissolution. Stabilizers are significant constituents of nanosuspensions. Herein we presented computational research on screening stabilizers and exploring stabilization mechanisms. The crystal transformation mechanism was also investigated. Soluplus-P407 and TPGS-HPMCE5 were screened by spatial conformation and thermodynamic energy analyses. The prepared nanosuspensions improved the dissolution properties of bulk drugs at pH 1.2, 4.5, 6.8. The nanosuspensions stabilization mechanism was analyzed by Molecular docking, Molecular dynamics simulations, Fourier transform infrared spectroscopy and Raman spectroscopy. It might be relate to the decreased enthalpy and Gibbs free energy which were determined by the synergy of external and internal energy factors. The X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy and transmission electron microscopy showed the crystal structures. The irbesartan B form was transformed in a Soluplus-P407-B/TPGS-HPMCE5-B physical mixture, but not in an SDS (–OH free)-B physical mixture. The intra-proton transfer induced by –OH on the stabilizer might be the transformation mechanism.

Effect of mutation of NS2B cofactor residues on Dengue 2 NS2B-NS3 protease complex – an insight to viral replication

Dengue fever is an endemic virus-borne disease that causes many severe ailments, including dengue hemorrhagic fever and dengue shock syndrome. NS2B-NS3 protease is present in all four strains of the dengue virus. NS2B-NS3 is a non-structural protein that performs three distinct functions: protease activity, helicase activity, and nucleoside triphosphatase activity. NS2B-NS3 pro-complex plays a crucial role in viral replication, and NS2B interacts with NS3 protease at a flat active site with an amino acid of the N-terminal region. NS2B acts as a cofactor for NS3 protease. In the current study, the conserved residues of NS2B were identified. Dengue virus-2 NS2B was mutated at the identified conserved amino acid region to investigate the role of NS2B on activation of NS3 pro. Molecular dynamics simulations were performed to investigate the mutated complex’s changes in stability, conformation, and free energy. The EAG mutant complex exhibited more unstable conformation, less hydrogen bond formation, and high binding energy than wild type. This result suggests a vital role of E63, A65, G69 mutation in NS2B for the interruption of activation of the NS3. Communicated by Ramaswamy H. Sarma

Quantitative Analysis of Protein Corona on Precoated Protein Nanoparticles and Determined Nanoparticles with Ultralow Protein Corona and Efficient Targeting in Vivo.

The protein corona on nanoparticles (NPs) is a critical problem that often screens the targeting molecules and becomes one of the key reasons for the lack of practical application in nanotherapy. It is critical to fully understand the mechanism of the nanoparticle-biological interactions to design the nanoparticle-based therapeutic agents. Some types of proteins can be precoated on the nanoparticles to avoid unwanted protein attachment; however, the ultralow level of protein corona is hard to achieve, and the relationship of the antifouling property of the precoated protein nanoparticles with protein conformation and protein-nanoparticle interaction energy has never been investigated. In this work, we provided the quantitative protein corona composition analysis on different precoated protein nanoparticles, and on the basis of the molecular simulation process, we found their antifouling property strongly depended on the interaction energy of the precoated protein-serum protein pair and the number of hydrogen bonds formed between them. Furthermore, it also depended on the nanoparticle-serum protein pair interaction energy and the protein conformation on the nanoparticle. The casein coated nanoparticle with the antifouling property was determined, and after aptamer conjugation and drug loading, they exhibited superior targeting and internalization behavior for photodynamic and photothermal therapy in vitro and in vivo. Our work adds to the understanding of the protein corona behavior of precoated protein nanoparticles, and the determined antifouling NP can potentially be used as a highly efficient nanodrug carrier.

Basic physicochemical processes governing self‐healable polymers†

AbstractThis short review outlines basic chemical and physical principles that can be utilized in the development of self‐healing polymers. Physical processes include the interdiffusion of polymer chains, the introduction of phase‐separated morphologies, shape memory effects or incorporating active nanoparticles into a polymer matrix. Dynamic covalent, free radical or supramolecular bonds are predominantly chemical processes. However, self‐healing will also involve a combination of physical and chemical events, such as taking advantage of enhanced van der Waals forces resulting in inter‐digitated copolymer morphologies or embedded reactive encapsulated fluids that burst open upon damage to fill up a wound. Sufficient molecular mobility for autonomous self‐healing under ambient conditions can also be achieved while maintaining high strength and stiffness in precisely designed commodity polymers. The efficient storage and recovery of conformational entropic energy stored during damage or excess of surface energy resulting from damage will drive the reduction of newly generated interfaces created upon damage by shallowing and widening wounds until healed. © 2021 Society of Industrial Chemistry.

GPU acceleration of rank-reduced coupled-cluster singles and doubles.

We have developed a graphical processing unit (GPU) accelerated implementation of our recently introduced rank-reduced coupled-cluster singles and doubles (RR-CCSD) method. RR-CCSDintroduces a low-rank approximation of the doubles amplitudes. This is combined with a low-rank approximation of the electron repulsion integrals via Cholesky decomposition. The result of these two low-rank approximations is the replacement of the usual fourth-order CCSDtensors with products of second- and third-order tensors. In our implementation, only a single fourth-order tensor must be constructed as an intermediate during the solution of the amplitude equations. Owing in large part to the compression of the doubles amplitudes, the GPU-accelerated implementation shows excellent parallel efficiency (95% on eight GPUs). Our implementation can solve the RR-CCSDequations for up to 400 electrons and 1550 basis functions-roughly 50% larger than the largest canonical CCSDcomputations that have been performed on any hardware. In addition to increased scalability, the RR-CCSDcomputations are faster than the corresponding CCSDcomputations for all but the smallest molecules. We test the accuracy of RR-CCSDfor a variety of chemical systems including up to 1000 basis functions and determine that accuracy to better than 0.1% error in the correlation energy can be achieved with roughly 95% compression of the ov space for the largest systems considered. We also demonstrate that conformational energies can be predicted to be within 0.1kcal mol-1 with efficient compression applied to the wavefunction. Finally, we find that low-rank approximations of the CCSDdoubles amplitudes used in the similarity transformation of the Hamiltonian prior to a conventional equation-of-motion CCSDcomputation will not introduce significant errors (on the order of a few hundredths of an electronvolt) into the resulting excitation energies.

Coordinated Actions of Cas9 HNH and RuvC Nuclease Domains Are Regulated by the Bridge Helix and the Target DNA Sequence.

CRISPR-Cas systems are RNA-guided nucleases that provide adaptive immune protection in bacteria and archaea against intruding genomic materials. Cas9, a type-II CRISPR effector protein, is widely used for gene editing applications since a single guide RNA can direct Cas9 to cleave specific genomic targets. The conformational changes associated with RNA/DNA binding are being modulated to develop Cas9 variants with reduced off-target cleavage. Previously, we showed that proline substitutions in the arginine-rich bridge helix (BH) of Streptococcus pyogenes Cas9 (SpyCas9-L64P-K65P, SpyCas92Pro) improve target DNA cleavage selectivity. In this study, we establish that kinetic analysis of the cleavage of supercoiled plasmid substrates provides a facile means to analyze the use of two parallel routes for DNA linearization by SpyCas9: (i) nicking by HNH followed by RuvC cleavage (the TS (target strand) pathway) and (ii) nicking by RuvC followed by HNH cleavage (the NTS (nontarget strand) pathway). BH substitutions and DNA mismatches alter the individual rate constants, resulting in changes in the relative use of the two pathways and the production of nicked and linear species within a given pathway. The results reveal coordinated actions between HNH and RuvC to linearize DNA, which is modulated by the integrity of the BH and the position of the mismatch in the substrate, with each condition producing distinct conformational energy landscapes as observed by molecular dynamics simulations. Overall, our results indicate that BH interactions with RNA/DNA enable target DNA discrimination through the differential use of the parallel sequential pathways driven by HNH/RuvC coordination.

Structural and Energetic Properties of Amino Acids and Peptides Benchmarked by Accurate Theoretical and Experimental Data.

Structural, energetic, and spectroscopic data derived in this work aim at the setup of an "experimentally validated" database for amino acids and polypeptides conformers. First, the "cheap" composite scheme (ChS, CCSD(T)/(CBS+CV)MP2) is tested for evaluation of conformational energies of all eight stable conformers of glycine, by comparing to the more accurate CCSD(T)/CBS+CV computations (Phys. Chem. Chem. Phys. 2013, 15, 10094-10111 and J Mol. Model. 2020, 26, 129). The recently proposed jun-ChS (J. Chem. Theory and Comput. 2020, 16, 988-1006), employing the jun-cc-pVnZ basis set family for CCSD(T) computations and CBS extrapolation, yields conformational energies accurate to 0.2 kJ·mol-1, at reduced computational cost with respect to aug-ChS employing aug-cc-pVnZ basis sets. The jun-ChS composite scheme is further applied to derive conformational energies for three dipeptide analogues Ac-Gly-NH2, Ac-Ala-NH2, and Gly-Gly. Finally, dipeptide conformational energies and semiexperimental equilibrium rotational constants along with the CCSD(T)/(CBS+CV)MP2 structural parameters (J. Phys. Chem. Lett. 2014, 5, 534-540) stand as the reference for benchmarking of selected density functional methodologies. The double-hybrid functionals B2-PLYP-D3(BJ) and DSD-PBEP86, perform best for structural and energetic characterization of all dipeptide analogues. From hybrid functionals CAM-B3LYP-D3(BJ) and ωB97X-D3(BJ) represent promising methods applicable for larger peptide-based systems for which computations with double-hybrid functionals are not feasible.

A molecular view of plasticization of polyvinyl alcohol.

Although macromolecules such as polymers are in widespread industrial use, pure formulations rarely have precisely the properties new applications demand. Pure polymer is often too brittle and inflexible, necessitating plasticizers to soften or toughen films and bulk polymer materials. In practice, new formulations are developed by extensive trial-and-error methods, as no general molecular explanations exist for the mechanism of plasticization to aid in determining the optimal structure and concentration of plasticizers. Here, through atomistic molecular simulations augmented with advanced sampling techniques, we develop an atomic-level picture of the processes in plasticization by directly calculating free energies that govern the interaction between polymers and small-molecule plasticizers. This work focuses on the influence of two common plasticizer molecules-glycerol and sorbitol-interacting with polyvinyl alcohol (PVA), a frequently used component of polymer films. In particular, we focus on conformational and hydrogen bond structure changes induced in globules of PVA by the plasticizer molecules, with the hypothesis that hydrogen bonding plays a role in the incorporation of these plasticizers into PVA and, thus, in the observed mechanical properties. While we focus on nanoscopic systems, we observe distinct preferences in the conformational free energy that can be connected to the performance of polymer materials at laboratory and industrial scales. This work presents a new molecular perspective from which effective plasticizers can be developed and presents a firm basis from which important analyses of plasticization in complex chemical environments relevant to industry may be developed.