Mechanism Of Selective Binding Research Articles

Site-specific albumin tagging with chloride-containing near-infrared cyanine dyes: molecular engineering, mechanism, and imaging applications.

Near-infrared dyes, particularly cyanine dyes, have shown great potential in biomedical imaging due to their deep tissue penetration, high resolution, and minimal tissue autofluorescence/scattering. These dyes can be adjusted in terms of absorption and emission wavelengths by modifying their chemical structures. The current issues with cyanine dyes include aggregation-induced quenching, poor photostability, and short in vivo circulation time. Encapsulating cyanine dyes with albumin, whether exogenous or endogenous, has been proven to be an effective strategy for improving their brightness and pharmacokinetics. In detail, the chloride-containing (Cl-containing) cyanine dyes have been found to selectively bind to albumin to achieve site-specific albumin tagging, resulting in enhanced optical properties and improved biosafety. This feature article provides an overview of the progress in the covalent binding of Cl-containing cyanine dyes with albumin, including molecular engineering methods, binding sites, and the selective binding mechanism. The improved optical properties of cyanine dyes and albumin complexes have led to cutting-edge applications in biological imaging, such as tumor imaging (diagnostics) and imaging-guided surgery.

The binding model of adenosine-specific DNA aptamer: Umbrella sampling study

We report a novel model of the selective binding mechanism of adenosine-specific DNA aptamer. Our theoretical investigations of AMP (Adenosine monophosphate) dissociation from aptamer-AMP complexes reveals new details of aptamer molecular specificity and stabilisation factors. Umbrella sampling MD calculations using parmbsc1 force field shows that the disordered structure of the internal loop of the unbound aptamer hairpin has a characteristic packing of guanines, which prevents barrier-free penetration of ligands into the site cavity. Also, this disordered structure of the unbound aptamer has a network of hydrogen bonds stabilising the cavity near the target guanines within the binding sites during the whole binding process. We suggested that the first AMP molecule binds to the disordered structure of the site closest to the aptamer hairpin stem and spends some free energy on ordering of the internal loop. Then the second AMP molecule binds to the ordered site closest to the aptamer hairpin loop with a lower energy gain. As a result, the induced-fit binding model is the most applicable for this aptamer and does not contradict the modern experimental NMR and calorimetry data.

Computational analysis of PTP-1B site-directed mutations and their structural binding to potential inhibitors

Protein tyrosine phosphatase-1B (PTP-1B) is a well-known therapeutic target for diabetes and obesity as it suppresses insulin and leptin signaling. PTP-1B deletion or pharmacological suppression boosted glucose homeostasis and insulin signaling without altering hepatic fat storage. Inhibitors of PTP-1B may be useful in the treatment of type 2 diabetes, and shikonin, a naturally occurring naphthoquinone dye pigment, is reported to inhibit PTP-1B and possess antidiabetic properties. Since the cell contains a large number of phosphatases, PTP-1B inhibitors must be effective and selective. To explore more about the mechanism underlying the inhibitor's efficacy and selectivity, we investigated its top four pharmacophores and used site-directed mutagenesis to insert amino acid mutations into PTP-1B as an extension of our previous study where we identified 4 pharmacophores of shikonin. The study aimed to examine the site-directed mutations like R24Y, S215E, and S216C influence the binding of shikonin pharmacophores, which act as selective inhibitors of PTP-1B. To achieve this purpose, docking and molecular dynamics simulations of wild-type (WT) and mutant PTP-1B with antidiabetic compounds were undertaken. The simulation results revealed that site-directed mutations can change the hydrogen bond and hydrophobic interactions between shikonin pharmacophores and many residues in PTP-1B's active site, influencing the drug's binding affinity. These findings could aid researchers in better understanding PTP-1B inhibitors' selective binding mechanism and pave the path for the creation of effective PTP-1B inhibitors.

Exploring PI3Kγ binding preference with Eganelisib, Duvelisib, and Idelalisib via energetic, pharmacophore and dissociation pathway analyses

Phosphatidylinositol 3-kinase (PI3K) is the central regulator of cellular functions and is suggested as a target for various diseases; thus, effective PI3K inhibitors provide a promising opportunity for the pharmaceutical intervention of many diseases. Among them, PI3Kγ has received more attention because of its essential role in immune signaling. However, the development of novel selective PI3Kγ inhibitors is a major challenge due to the high sequence homology across the class I PI3K isoforms. Therefore, understanding the substrate specificity and receptor-ligand interaction of PI3Kγ would be an appropriate strategy for the rational design of potent γ-selective inhibitors. In this study, by combining various molecular modeling approaches (including classic and enhanced sampling molecular dynamics (MD) simulations, end-point binding free energy calculations, and pharmacophore models), three quinolinone core-containing inhibitors, Idelalisib/CAL-101, Duvelisib/IPI-145, and Eganelisib/IPI-549, were employed to reveal the selective binding mechanisms targeting PI3Kγ. The classic MD and free energy calculations highlight the significant interaction and some key residues for the selective binding against PI3Kγ. Furthermore, the dissociation pathway analysis based on umbrella sampling simulations reveals that hydrophobic interactions are dominant for binding of the three ligands during the dissociation processes, and cooperation between the P-loop and the ligands always exists in the binding/dissociation process. Finally, the pharmacophore model revealed that IPI-549 contains a unique hydrophobic feature, and PI3Kγ exhibits an important hydrogen bond donor feature of hydrogen amide. These findings may provide some important information for the rational design and optimization of PI3Kγ-selective inhibitors.

Molecular Modeling and Molecular Dynamics Simulation Studies on the Selective Binding Mechanism of MTHFD2 Inhibitors

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme that plays an important role in purinecarbon metabolism and thymidine biosynthesis. It has attracted broad interest as a novel therapeutic target for cancer. However, a major problem of current MTHFD2 inhibitors is their lack of selectivity and reactivity with its closest isoform, MTHFD1. Recently, the first selective MTHFD2 inhibitor, DS44960156, has been reported and it exhibits a more than 18-fold selectivity for MTHFD2 over MTHFD1. However, mechanism of DS44960156 selective binding to MTHFD2 over MTHFD1 is unknown. In this study, molecular docking, molecular dynamics (MD) simulations, molecular mechanics generalized born/surface area (MM_GBSA) binding free energy calculations, and analysis of the decomposition of binding free energies were used to investigate the selective binding mechanism of DS44960156 to the folate-binding site of MTHFD2 over MTHFD1. The results revealed that contributions from residues Gln100/Gln132, Val55/Asn87, and Gly237/Gly310 in the binding pocket of MTHFD1/MTHFD2 are the key factors responsible for the binding selectivity. These findings explain the selectivity of DS44960156 to MTHFD2 over MTHFD1, and may provide guidance for the future study and design of novel MTHFD2 inhibitors.

Molecular mechanism of anionic stabilizer for telomere G-quadruplex.

Telomere DNA assumes a high-order G-quadruplex (G4) structure, stabilization of which prevents telomere lengthening by telomerase in cancer. Through applying combined molecular simulation methods, an investigation on the selective binding mechanism of anionic phthalocyanine 3,4',4'',4'''-tetrasulfonic acid (APC) and human hybrid (3 + 1) G4s was firstly performed at the atomic level. Compared to the groove binding mode of APC and the hybrid type I (hybrid-I) telomere G4, APC preferred to bind to the hybrid type II (hybrid-II) telomere G4 via end-stacking interactions, which showed much more favorable binding free energies. Analyses of the non-covalent interaction and binding free energy decomposition revealed a decisive role of van der Waals interaction in the binding of APC and telomere hybrid G4s. And the binding of APC and hybrid-II G4 that showed the highest binding affinity adopted the end-stacking binding mode to form the most extensive van der Waals interactions. These findings add new knowledge to the design of selective stabilizers targeting telomere G4 in cancer.

Theoretically exploring selective-binding mechanisms of BRD4 through integrative computational approaches

ABSTRACT The origin of cancer is related to the dysregulation of multiple signal pathways and of physiological processes. Bromodomain-containing protein 4 (BRD4) has become an attractive target for the development of anticancer and anti-inflammatory agents since it can epigenetically regulate the transcription of growth-promoting genes. The synthesized BRD4 inhibitors with new chemical structures can reduce the drug resistance, but their binding modes and the inhibitory mechanism remain unclear. Here, we initially constructed robust QSAR models based on 68 reported tetrahydropteridin analogues using topomer CoMFA and HQSAR. On the basis of QSAR results, we designed 16 novel tetrahydropteridin analogues with modified structures and carried out docking studies. Instead of significant hydrogen bondings with amino acid residue Asn140 as reported in previous research, the molecular docking modelling suggested a novel docking pose that involves the amino acid residues (Trp81, Pro82, Val87, Leu92, Leu94, Cys136, Asp144, and Ile146) at the active site of BRD4. The MD simulations, free energy calculations, and residual energy contributions all indicate that hydrophobic interactions are decisive factors affecting bindings between inhibitors and BRD4. The current study provides new insights that can aid the discovery of BRD4 inhibitors with enhanced anti-cancer ability.

Molecular insights into the selective binding mechanism targeting parallel human telomeric G-quadruplex

Stabilizing human telomere DNA G-quadruplex (G4) proves a promising anti-cancer strategy. Though plenty of G4 stabilizing molecules have been reported, little is known about their selective binding mechanism among various G4s. Recently, a designed monohydrazone derivative (compound 15) was reported to display specific preference in binding and stabilizing parallel human telomeric G4. To reveal the selective binding mechanism, a comparative theoretical investigation was performed on two monohydrazone derivatives (compounds 1 and 15) and three telomeric G4s showing parallel, hybrid-I, and hybrid-II conformations. Two probable binding modes, i.e. the end-stacking binding and the groove binding, were predicted by molecular dockings for each monohydrazone in its binding with the telomeric G4s. Further long-timescale molecular dynamics simulations reveal the conversion from the groove binding to the end-stacking binding for both compounds, indicating the preference of the end-stacking binding mode. Structural analysis together with binding free energy calculations show that the van der Waals interaction plays a leading role in ranking the binding affinity. By forming extensive van der Waals interactions, the parallel G4–15 binding complex shows the highest binding affinity, and the corresponding compound 15 exhibits the strongest stabilizing effect to the telomeric G4. These findings agree well with the experimental observations. Through characterizing the selective binding between monohydrazones and telomeric G4s at the atomic level, the current study provides support to the design of novel selective stabilizers targeting telomeric G4s.

Deciphering the selective binding mechanisms of anaplastic lymphoma kinase–derived neuroblastoma tumor neoepitopes to human leukocyte antigen

Neuroblastoma (NB), as a metastatic form of solid tumor, has a high fatality rate found in early childhood. The two anaplastic lymphoma kinase (ALK) neoepitopes nonamer and decamer used in cancer immunotherapy against NB cancer can selectively bind to the human leukocyte antigen (HLA-B*15:01) groove with high affinities, whereas the native self-peptide is unable to interact with the HLA-B*15:01. Here, we performed molecular dynamics (MD) simulations and subsequent molecular mechanics-generalized born surface area (MM-GBSA) binding free energy calculations to explore the selective binding mechanisms of nonamer and decamer to the HLA-B*15:01 against the self-peptide. MD simulations revealed the significant conformational dynamics of the self-peptide in the HLA-B*15:01 groove against the nonamer and decamer. Binding free energy calculations showed that the binding affinities of HLA-B*15:01-neoepitope complexes were followed in the order decamer > nonamer > self-peptide. Detailed analysis of HLA-B*15:01-neoepitope structural complexes showed that compared to the nonamer, the self-peptide tended to move outward to the solvent, whereas the decamer moved deep to the HLA-B*15:01 groove. These different dynamic observations of the ALK neoepitopes can explain the distinct binding affinities of self-peptide, nonamer, and decamer to the HLA-B*15:01. The results may be useful for the design of more selective ALK neoepitopes.

Computational investigation of the selectivity mechanisms of PI3Kδ inhibition with marketed idelalisib: combined molecular dynamics simulation and free energy calculation

Phosphoinositide 3-kinase (PI3K) has been considered to be a potential drug target for the treatment of several human body diseases. Nowadays, great efforts have been made on the development of selective PI3Kδ inhibitors because of the FDA approval of idelalisib, which is the first listed PI3K inhibitor. But serious side effects occur during the use of idelalisib that greatly promotes the development of novel PI3Kδ inhibitors. Nevertheless, idelalisib is still an important milestone in the development of selective PI3Kδ inhibitors, but the detailed selective binding mechanisms between idelalisib and PI3Ks have not been well elucidated. Therefore, in this study, an integrated modeling strategy combining molecular docking, molecular dynamics simulation, and free energy calculation was performed to reveal the molecular-level binding mechanisms of idelalisib and class I PI3K. First, molecular docking was carried on to obtain a reasonable binding posture of idelalisib in different PI3K isoforms. Then, key residues for selective inhibition of PI3Kδ were highlighted by molecular dynamics simulation and energy calculations. Finally, idelalisib was also compared with its lead compound, IC87114, to reveal the reason for the higher potency of Idelalisib for PI3Kδ. We hope that this study would provide some guidance for the rational design of selective PI3Kδ inhibitors.

Molecular Mechanism of Selective Binding of NMS-P118 to PARP-1 and PARP-2: A Computational Perspective.

The nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have been proven effective to potentiate both chemotherapeutic agents and radiotherapy. However, a major problem of most current PARP inhibitors is their lack of selectivity for PARP-1 and its closest isoform PARP-2. NMS-P118 is a highly selective PARP inhibitor that binds PARP-1 stronger than PARP-2 and has many advantages such as excellent pharmacokinetic profiles. In this study, molecular dynamics (MD) simulations of NMS-P118 in complex with PARP-1 and PARP-2 were performed to understand the molecular mechanism of its selectivity. Alanine scanning together with free energy calculation using MM/GBSA and interaction entropy reveal key residues that are responsible for the selectivity. Although the conformation of the binding pockets and NMS-P118 are very similar in PARP-1 and PARP-2, most of the hot-spot residues in PARP-1 have stronger binding free energy than the corresponding residues in PARP-2. Detailed analysis of the binding energy shows that the 4′4-difluorocyclohexyl ring on NMS-P118 form favorable hydrophobic interaction with Y889 in PARP-1. In addition, the H862 residue in PARP-1 has stronger binding free energy than H428 in PARP-2, which is due to shorter distance and stronger hydrogen bonds. Moreover, the negatively charged E763 residue in PARP-1 forms stronger electrostatic interaction energy with the positively charged NMS-P118 than the Q332 residue in PARP-2. These results rationalize the selectivity of NMS-P118 and may be useful for designing novel selective PARP inhibitors.

Exploration of the selective binding mechanism of GSK3β via molecular modeling and molecular dynamics simulation studies

Kinase inhibitor selectivity is a major concern for the design of small-molecule compounds. As a member of serine/threonine protein kinase family, glycogen synthase kinase 3β (GSK3β) is involved in diverse biological processes and abnormal dysregulation of its activity has been associated with several pathologies, including type II diabetes, Alzheimer’s disease, bipolar disorders, and cancers. A small-molecule PF-367 significantly inhibited the GSK3 enzymatic activity over its closest cyclin-dependent kinase 2 (CDK2) with >1000-fold selectivity. However, the PF-367 selectively binding to GSK3β over CDK2 has remained unclear. Here, molecular docking, molecular dynamics (MD) simulations, and molecular mechanics_generalized born/surface area (MM_GBSA) binding free energy calculations, as well as the decomposition of binding free energies were performed to investigate the selective binding mechanism of PF-367 to the ATP-binding site of GSK3β over CDK2. The results revealed that the exposure of the terminal triazole ring of PF-367 into the solvent environment may be responsible for the weak binding complex of CDK2−PF-367, which was further confirmed by the binding free energy calculations and the identified key residues (Phe67, Lys85, Thr138, and Arg141) contributing to the binding interaction. The obtained data can not only decipher the origin of selectivity, but also be used for the design of more potent and selective GSK3β inhibitors.

Exploration of the selective binding mechanism of protein kinase Aurora A selectivity via a comprehensive molecular modeling study.

BackgroundThe kinase of Aurora A has been regarded as a promising therapeutic target due to its altered expression in various human cancers. However, given the high similarity of the active binding site of Aurora A to other kinases, designing highly selective inhibitors towards Aurora A remains a challenge. Recently, two potential small-molecule inhibitors named AT9283 and Danusertib were reported to exhibit significant selectivity to Aurora A, but not to Gleevec. It was argued that protein dynamics is crucial for drug selectivity to Aurora A. However, little computational research has been conducted to shed light on the underlying mechanisms.MethodsIn this study, MM/GBSA calculations based on conventional molecular dynamics (cMD) simulations and enhanced sampling simulations including Gaussian accelerated MD (GaMD) simulations and umbrella sampling were carried out to illustrate the selectivity of inhibitors to Aurora A.ResultsThe calculation results from cMD simulation showed that the binding specificity is primarily controlled by conformational change of the kinase hinge. The protein dynamics and energetic differences were further supported by the GaMD simulations. Umbrella sampling further proved that AT9283 and Danusertib have similar potential of mean force (PMF) profiles toward Aurora A in terms of PMF depth. Compared with AT9283 and Danusertib, Gleevec has much lower PMF depth, indicating that Gleevec is more easily dissociated from Aurora A than AT9283 and Danusertib. These results not only show the selective determinants of Aurora A, but also provide valuable clues for the further development of novel potent Aurora A selective inhibitors.

Theoretical studies on the selectivity mechanisms of PI3Kδ inhibition with marketed idelalisib and its derivatives by 3D-QSAR, molecular docking, and molecular dynamics simulation.

Phosphoinositide 3-kinases (PI3Ks) are crucial for cell proliferation, metabolism, motility, and cancer progression. Since the selective PI3Kδ inhibitor, idelalisib, was firstly approved by the FDA in 2014, large numbers of selective PI3Kδ inhibitors have been reported, but the detailed mechanisms of selective inhibition to PI3Kδ for idelalisib or its derivatives have not been well addressed. In this study, 3D-QSAR with COMFA, molecular docking, and molecular dynamic (MD) simulations was used to explore the binding modes between PI3Kδ and idelalisib derivatives. Firstly, a reliable COMFA model (q2 = 0.59, ONC = 8, r2 = 0.966) was built and the contour maps showed that the electrostatic field had more significant contribution to the bioactivities of inhibitors. Secondly, two molecular docking methods including rigid receptor docking (RRD) and induced fit docking (IFD) were employed to predict the docking poses of all the studied inhibitors and revealed the selective binding mechanisms. And then, the results of the MD simulation and the binding free energy decomposition verified that the binding of PI3Kδ/inhibitors was mainly contributed from hydrogen bonding and hydrophobic interactions and some key residues for selective binding were highlighted. Finally, based on the models developed, 14 novel inhibitors were optimized and some showed satisfactory predicted bioactivity. Taken together, the results provided by this study may facilitate the rational design of novel and selective PI3Kδ inhibitors. Graphical abstract .

Molecular Dynamics Simulations of A27S and K120A Mutated PTP1B Reveals Selective Binding of the Bidentate Inhibitor.

Protein tyrosine phosphatase 1B (PTP1B) is considered a potential target for the treatment of type II diabetes and obesity due to its critical negative role in the insulin signaling pathway. However, improving the selectivity of PTP1B inhibitors over the most closely related T-cell protein tyrosine phosphatase (TCPTP) remains a major challenge for inhibitor development. Lys120 at the active site and Ser27 at the second pTyr binding site are distinct in PTP1B and TCPTP, which may bring differences in binding affinity. To explore the determinant of selective binding of inhibitor, molecular dynamics simulations with binding free energy calculations were performed on K120A and A27S mutated PTP1B, and the internal changes induced by mutations were investigated. Results reveal that the presence of Lys120 induces a conformational change in the WPD-loop and YRD-motif and has a certain effect on the selective binding at the active site. Ser27 weakens the stability of the inhibitor at the second pTyr binding site by altering the orientation of the Arg24 and Arg254 side chains via hydrogen bonds. Further comparison of alanine scanning demonstrates that the reduction in the energy contribution of Arg254 caused by A27S mutation leads to a different inhibitory activity. These observations provide novel insights into the selective binding mechanism of PTP1B inhibitors to TCPTP.

Insight into the selective binding mechanism of DNMT1 and DNMT3A inhibitors: a molecular simulation study.

DNA methyltransferases (DNMTs), responsible for the regulation of DNA methylation, have been regarded as promising drug targets for cancer therapy. However, high structural conservation of the catalytic domains of DNMTs poses a big challenge to design selective inhibitors for a specific DNMT isoform. In this study, molecular dynamics (MD) simulations, end-point free energy calculations and umbrella sampling (US) simulations were performed to reveal the molecular basis of the binding selectivity of three representative DNMT inhibitors towards DNMT1 and DNMT3A, including SFG (DNMT1 and DNMT3A dual inhibitors), DC-05 (DNMT1 selective inhibitor) and GSKex1 (DNMT3A selective inhibitor). The binding selectivity of the studied inhibitors reported in previous experiments is reproduced by the MD simulation and binding free energy prediction. The simulation results also suggest that the driving force to determine the binding selectivity of the studied inhibitors stems from the difference in the protein-inhibitor van der Waals interactions. Meanwhile, the per-residue free energy decomposition reveals that the contributions from several non-conserved residues in the binding pocket of DNMT1/DNMT3A, especially Val1580/Trp893, Asn1578/Arg891 and Met1169/Val665, are the key factors responsible for the binding selectivity of DNMT inhibitors. In addition, the binding preference of the studied inhibitors was further validated by the potentials of mean force predicted by the US simulations. This study will provide valuable information for the rational design of novel selective inhibitors targeting DNMT1 and DNMT3A.

A Residue outside the Binding Site Determines the Gα Binding Specificity of GoLoco Motifs

GoLoco motif-containing proteins regulate the nucleotide-binding state of Gα proteins in various signaling pathways. As guanine nucleotide dissociation inhibitors (GDIs), they bind Gα·GDP and inhibit GDP to GTP exchange. GoLoco proteins show binding selectivity toward different members of the Gα family. Although the Gαi1·GDP/RGS14 crystal structure explains the specific binding selectivity of the RGS14 GoLoco domain well, the mechanism of selective binding has not been understood for the more general features of short GoLoco domains found in tandem arrays in proteins like GPSM2/LGN/ dPins and GPSM1/AGS3. We explored the mechanism of differential interactions of GoLoco protein LGN with hGαi3 and hGαo. By combining mutagenesis experiments and molecular dynamics simulations, we identified a residue (Asp229 in hGαi3) away from the binding interface that remarkably affects the interaction between LGN and hGαi/o. A negatively charged residue at this position is required for high binding affinity. This affinity regulation mechanism was further verified by the cases of hGαi2 and dGαo, suggesting that this pathway is conserved among members of the Gα family.

Structural insights into modulation and selectivity of transsynaptic neurexin\u2013LRRTM interaction

Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) function as postsynaptic organizers that induce excitatory synapses. Neurexins (Nrxns) and heparan sulfate proteoglycans have been identified as presynaptic ligands for LRRTMs. Specifically, LRRTM1 and LRRTM2 bind to the Nrxn splice variant lacking an insert at the splice site 4 (S4). Here, we report the crystal structure of the Nrxn1β–LRRTM2 complex at 3.4 Å resolution. The Nrxn1β–LRRTM2 interface involves Ca2+-mediated interactions and overlaps with the Nrxn–neuroligin interface. Together with structure-based mutational analyses at the molecular and cellular levels, the present structural analysis unveils the mechanism of selective binding between Nrxn and LRRTM1/2 and its modulation by the S4 insertion of Nrxn.

Contrast agents for optical diagnostics of early osteoarthritis

The work is focused on the recent advances in the development of contrast agents for optical diagnostics of early osteoarthritis (OA). Optical imaging provides the high spatial resolution and may be useful for evaluation of submicron degenerative changes of cartilage structure unavailable for diagnosis by conventional radiography and magnetic resonance tomography (MRT). To increase the contrast and sensitivity of optical signal the specific absorbing additives are being developed: targeted and non-targeted fluorescent probes, functionalized metallic and polymeric nanoparticles (NPs). Sometimes the diagnostic and therapeutic potentials are bringing together in one substance thus providing increased effectiveness of the early prevention of OA. Also, the theoretical aspects of selective binding mechanisms to the tissue degenerative sites are briefly concerned.

Selective solute adsorption and partitioning around single PNIPAM chains.

Thermoresponsive polymer architectures have become integral building blocks of 'smart' functional materials in modern applications. For a large range of developments, e.g. for drug delivery or nanocatalytic carrier systems, the selective adsorption and partitioning of molecules (ligands or reactants) inside the polymeric matrix are key processes that have to be controlled and tuned for the desired material function. In order to gain insights into the nanoscale structure and binding details in such systems, we here employ molecular dynamics simulations of the popular poly(N-isopropylacrylamide) (PNIPAM) polymer in explicit water in the presence of various representative solute types with a focus on aromatic model reactants. We study a single polymer chain and explore the influence of its elongation, stereochemistry, and temperature on the solute binding affinities. While we find that the excess adsorption generally increases with the size of the solute, the temperature-dependent affinity to the chain is highly solute specific and has a considerable dependence on the polymer elongation (i.e. polymer swelling state). We elucidate the molecular mechanisms of the selective binding in detail and eventually present how the results can be extrapolated to macroscopic partitioning of the solutes in swollen polymer architectures, such as hydrogels.