The Journal of Physical Chemistry B最新文献

{"title":"Lysozyme in Mixtures of Hydrogen Bond Acceptor Solvents with Water: Enthalpies and Entropies of Preferential Solvation.","authors":"Vladimir A Sirotkin","doi":"10.1021/acs.jpcb.5c00304","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c00304","url":null,"abstract":"<p><p>The main focus of this work is to clarify how enzyme macromolecules become solvated in water-organic mixtures and to estimate the enthalpies and entropies of this solvation process. Isothermal calorimetry and water/organic solvent adsorption measurements were used to investigate the preferential solvation of hen egg white lysozyme in hydrogen bond acceptor solvents at 298.15 K. Dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, and acetone were used as model organic cosolvents. Preferential solvation was described by analyzing the excess thermodynamic functions of the mixing. The novelty of this approach is that the enthalpies and entropies of protein, water, and organic solvents can be simultaneously investigated across the entire range of water content. There are three composition regimes in water-organic mixtures. Stabilization of the protein as a result of the preferential hydration of lysozyme was detected in the water-rich region. Protein stabilization is driven by the positive change in entropy. The residual enzyme activity values are close to 100%, compared with those for pure water. In the intermediate region, lysozyme has a higher affinity for organic solvent molecules than for water. The cosolvent-induced inactivation of lysozyme was detected at intermediate water content, and residual enzyme activity is close to zero. At the lowest water content, the cosolvent molecules are preferentially excluded from the protein surface, resulting in preferential hydration and nonzero residual enzyme activity. In the water-poor region, protein stabilization is driven by the exothermic enthalpy change. The present study clearly demonstrates that the preferential solvation thermodynamic quantities strongly depend on the acceptance strength of the cosolvent hydrogen bond.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lateral Organization and Dynamics of the Realistic Plasma Membrane.","authors":"Tao Zhang, Jinrui Zhang, Huili Wang, Tianyi Zou, Sihang Cheng, Yang Yu, Junbo Wu, Yangang Pan, Xiaozheng Duan, Hongda Wang","doi":"10.1021/acs.jpcb.5c00909","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c00909","url":null,"abstract":"<p><p>Large-scale simulations of realistic crowded cell membranes can bridge the gap between the simulations and experiments. However, the compositional complexity and structural asymmetry of cell membranes continue to pose significant challenges in computational biology. Recent advances in understanding native membranes, including their composition and protein structures, enable us to construct a highly realistic model of the mammalian plasma membrane. Using this model, we explore the organization and dynamics of biological cell membranes at the molecular level. We found that the interaction preferences of protein-lipid mediate the formation of dynamic clusters of nonrandomly distributed proteins, accompanied by heterogeneous structural properties and anomalous diffusion. These evolving dynamic clusters intertwine to form a highly complex and continuously changing protein network. Our study provides significant insights into the intricate lateral dynamic organization of cell membranes.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Coarse-Grained Models to Describe the Self-Assembly of Aqueous Aerosol-OT","authors":"Alexander Moriarty,&nbsp;Takeshi Kobayashi,&nbsp;Teng Dong,&nbsp;Kristo Kotsi,&nbsp;Panagiota Angeli,&nbsp;Matteo Salvalaglio,&nbsp;Ian McRobbie and Alberto Striolo*,&nbsp;","doi":"10.1021/acs.jpcb.5c0047210.1021/acs.jpcb.5c00472","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c00472https://doi.org/10.1021/acs.jpcb.5c00472","url":null,"abstract":"<p >Aerosol-OT (AOT) is a very versatile surfactant that exhibits a plethora of self-assembly behaviors. In particular, due to its double-tail structure, it is capable of forming vesicles in water. However, the size of these structures, and the time scales over which they form, make them difficult to study using traditional all-atomistic molecular dynamics simulations. Here, three coarse-grained models are developed for AOT with different levels of detail. The models take advantage of the Martini 3 force field, which enables 2:1 mappings to be employed for the tail groups. It is shown that these models are able to reproduce the self-assembly behavior of AOT in water at three concentrations: below the critical vesicle concentration (CVC), above the CVC, and in the lamellar phase. The results also demonstrate the formation of vesicles from bicelles above the critical vesicle concentration, which is an important milestone for the continued study of vesicle behavior.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 21","pages":"5299–5310 5299–5310"},"PeriodicalIF":2.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jpcb.5c00472","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing Solvation within [l(-)-Menthol : Thymol] Deep Eutectic Solvents via Microfluidity Assessment.","authors":"Anushis Patra, Shreya Juneja, Siddharth Pandey","doi":"10.1021/acs.jpcb.5c01154","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01154","url":null,"abstract":"<p><p>Properties of deep eutectic solvents (DESs) can be effectively fine-tuned by judicious selection of the constituents and their relative amounts. The DESs prepared by mixing l(-)-menthol (Men) and thymol (Thy), two nonionic constituents, offer a nonpolar solvation environment desired in many chemical applications. These DESs are shown to exhibit temperature-dependent nonideality and possess complex intermolecular interactions dominated by sterically hindered H-bonded clusters. Key insights into solute solvation within the (Men : Thy) DES system are obtained by employing structurally different fluorescence microfluidity probes that operate based on different mechanisms. The (Men : Thy) DES system at nine (9) different molar ratios, from (5 : 1) to (1 : 5), in the temperature (<i>T</i>) range of 293 to 363 K is investigated using an intramolecular excimer-forming probe, two fluorescence anisotropy probes, and a fluorescence intensity-based microfluidity probe. The logarithm of microviscosity (ln <i>η</i>_μ) estimated from the response of the excimer-forming probe varies linearly with the logarithm of the bulk viscosity (ln <i>η</i>) across all nine compositions in the entire temperature range. Further, excellent linear correlation is observed between the rate constant (<i>k</i>_a) of the intramolecular excimer formation and <i>T</i>/<i>η</i> implying adherence to the Stokes-Einstein relationship. Rotational reorientation times (<i>θ</i>) obtained from the excited-state fluorescence anisotropy decay of the two structurally different probes follow the Perrin formulation (<i>θ</i> varying linearly with <i>η</i>/<i>T</i>) indicating the absence of significant microheterogeneity toward solute rotational diffusion within the (Men : Thy) DES system. The response of the fluorescence intensity (<i>I</i>_F) probe also exhibits a simple Arrhenius-type <i>T</i> dependence with <i>I</i>_F versus <i>η</i> for all DES compositions, fitting well to exponential growth-to-maxima. The solute solvation behavior observed from the responses of different fluorophores indicates a homogeneous solubilization environment afforded by the (Men : Thy) DES system that is independent of the composition and temperature. These findings have significant implications in chemical synthesis and analysis where such nonpolar DES systems have the potential to be effectively employed.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Size Dependent Liposomal Fusion and H-Bonded Sticky Aggregation Induced by Gold Nanoclusters","authors":"Mallika Mukherjee,&nbsp;Arunavo Chatterjee and Pradipta Purkayastha*,&nbsp;","doi":"10.1021/acs.jpcb.5c0105310.1021/acs.jpcb.5c01053","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01053https://doi.org/10.1021/acs.jpcb.5c01053","url":null,"abstract":"<p >We present a novel approach to quantitatively control liposomal fusion and aggregation, depending upon the surface charge and functionalities, using fluorescent gold nanoclusters (AuNCs). We show that ligand-protected ultrasmall AuNCs are excellent fusogenic materials that follow renal clearance pathways after induction of liposomal fusion, especially with dipalmitoylphosphatidylcholine (DPPC) and 1,2-dimyristoyl-<i>sn</i>-glycero-3-phosphoglycerol (DMPG) mixed in a 3:1 molar ratio mimicking the brain cells. AuNCs show interesting photophysics and emit from visible to near-infrared (NIR) regions depending upon the quantum confinement effect that is directly related to the Fermi wavelength and size of the NCs. Herein, we have synthesized orange-emitting <span>l</span>-glutathione (GSH) coated Au₂₅(GSH)₁₈ NCs (GSH-AuNCs) to be applied on lipid membranes to observe the fusogenic property on small and giant unilamellar vesicles (SUVs and GUVs). We noticed that the GSH-AuNCs easily attach to the surface of the DPPC liposomes and facilitate complete fusion through favorable lipid mixing. The fusion rate is higher (80%) for the DPPC SUVs compared to that for the GUVs, which has been explained experimentally. On the contrary, the DMPG SUVs aggregate, with minimal lipid mixing, in the presence of the GSH-AuNCs. We noted a ∼70% fusion efficiency for SUVs with mixed DPPC:DMPG composition (3:1 molar ratio). This is the first report on fusion and aggregation of liposomes guided by ligand functionalities and surface charge of AuNCs.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 21","pages":"5207–5216 5207–5216"},"PeriodicalIF":2.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrophobic Interactions in Aqueous Osmolyte Solutions: Thermodynamics of Solvation and Implication on Protein Stability","authors":"Cedrix J. Dongmo Foumthuim*,&nbsp;","doi":"10.1021/acs.jpcb.5c0078510.1021/acs.jpcb.5c00785","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c00785https://doi.org/10.1021/acs.jpcb.5c00785","url":null,"abstract":"<p >The effect of cosolvents urea and trimethylamine-<i>N</i>-oxide (TMAO) on hydrophobic association mechanisms is investigated by employing molecular dynamics simulations and free energy calculations. Three nonpolar moieties are used to model the hydrophobic interactions: <i>n</i>-hexane <i>n</i>C₆H₁₄, neopentane C₅H₁₂, and cyclohexane cC₆H₁₂. These hydrophobic model systems are subsequently immersed in four different solvent models with varied composition: pure water, aqueous urea, aqueous TMAO, and mixed urea-TMAO ternary solution. The solute–solute potentials of mean force (PMF), solute-water, and solute-cosolvent distribution functions are reported. Both urea and TMAO are found to have only moderate effects on hydrophobic associations, thereby mainly acting as glue bridging between pairwise hydrophobic moieties holding them together. Furthermore, it is seen that TMAO mediates the formation of hydrogen bonds between its oxygen atom and water or urea while still favoring the hydrophobic contacts with the hydrophobic surface, thereby acting as a kind of amphiphile displacing water or urea from the inner solvation shell of the hydrophobic solutes investigated here to the bulk. The analyses of the enthalpic and entropic contributions to PMFs indicate that configurations at the contact minimum are both enthalpically and entropically favorable, though, with a large entropic contribution, whereas solute-separated minimum configurations are dominantly enthalpically driven, induced by stabilizing water hydrogen bonding. To provide a more factual and general perspective to the simplistic hydrophobic models, simulations are also performed on a realistic-like hydrophobic model, β2-microglobulin (β2m), a paradigmatic protein model for amyloid studies. Results show that TMAO protects the β2m folded state by its strong preferential exclusion from the close vicinity of its surface. Contrariwise, urea moieties likely accumulate at the protein surface, thereby displacing water molecules from the hydration shell to the bulk, thus promoting an unfolded state of the protein.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 21","pages":"5150–5165 5150–5165"},"PeriodicalIF":2.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jpcb.5c00785","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the Possibility of Chiral Symmetry Breaking in Liquid Hydrogen Peroxide","authors":"Roberto Menta,&nbsp;Pablo G. Debenedetti,&nbsp;Roberto Car and Pablo M. Piaggi*,&nbsp;","doi":"10.1021/acs.jpcb.5c0178010.1021/acs.jpcb.5c01780","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01780https://doi.org/10.1021/acs.jpcb.5c01780","url":null,"abstract":"<p >Molecular chirality is a key concept in chemistry with implications for the origin of life and the manufacturing of pharmaceuticals. Previous simulations of a chiral molecular model with an energetic bias toward homochiral interactions show a spontaneous symmetry-breaking transition from a supercritical racemic liquid into a subcritical liquid enriched in one of the two enantiomers. Here, we employ molecular dynamics simulations in order to test the possible existence of this phenomenon in hydrogen peroxide, the smallest chiral molecule. For this purpose, we study the fluid phase of this substance between 100 and 1500 K, and from 100 kPa to 1 GPa. We find a glass transition and we suggest that hydrogen bonds play a central role in such behavior. We also test the possibility of observing chiral symmetry breaking by performing both constant temperature and cooling simulations at multiple pressures, and we do not observe the phenomenon. An analysis of the structure of the liquid shows negligible differences between homochiral and heterochiral interactions, supporting the difficulty in observing chiral symmetry breaking. If hydrogen peroxide manifests spontaneous chiral symmetry breaking, it likely takes place significantly below room temperature and is hidden by other phenomena, such as the glass transition or crystallization. More broadly, our results, and recent experimental observations, suggest that greater molecular complexity is needed for spontaneous chiral symmetry breaking in the liquid phase to occur.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 21","pages":"5335–5342 5335–5342"},"PeriodicalIF":2.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrolytic Degradation of Key Plastic Pollutant Model Systems by a Discrete Metal–Oxo Cluster: A Combined Theoretical and Experimental Study","authors":"Leonardo F. Serafim,&nbsp;Francisco de Azambuja,&nbsp;Parth Rathee,&nbsp;Lukun Wang,&nbsp;Tatjana N. Parac-Vogt* and Rajeev Prabhakar*,&nbsp;","doi":"10.1021/acs.jpcb.5c0125510.1021/acs.jpcb.5c01255","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01255https://doi.org/10.1021/acs.jpcb.5c01255","url":null,"abstract":"<p >Degradation of plastic materials represents one of the major challenges faced by the modern world. In this study, computational and experimental techniques have been employed to investigate the hydrolysis of most commonly used plastic materials poly(ether urethane) (PEU) and polyethylene terephthalate (PET) and their commercially available models ethyl <i>N</i>-phenylcarbamate (ENP) and ethylene glycol dibenzoate (EGD), respectively, by a discrete metal–oxo cluster, Zr-substituted Keggin-type polyoxometalate, (Et₂NH₂)₈[Zr(μ-O)(H₂O)(PW₁₁O₃₉)] (<b>ZrK</b>), in which the Zr(IV) catalytic site is stabilized by coordination to a robust metal–oxo core. The all-atom molecular dynamics simulations predicted that all substrates interact with <b>ZrK</b> through water-mediated interactions. The quantum mechanics/molecular mechanics (QM/MM) calculations showed that the lengths of scissile ester and amide bonds of PEU/ENP and the ester bond of PET/EGD are quite similar, and the hydrolysis of PEU and ENP and PET and EGD occurs with similar energetics. According to the most plausible mechanisms, the cleavage of the ester and amide bonds of PEU/ENP takes place with a barrier of 16.5/16.6 and 19.0/20.4 kcal/mol, respectively. However, the scissile ester bond of PET/EGD is hydrolyzed with a barrier of 16.7/16.5 kcal/mol. This computed difference in the rate-limiting barrier of 3.9 kcal/mol between the amide bond of ENP and the ester bond of EGD is supported by the experimentally observed sluggish hydrolysis of ENP in comparison to EGD. While both ENP and EGD were successfully hydrolyzed by <b>ZrK</b> in DMSO solvent at 100 °C, EGD hydrolysis has proven to be much more efficient, with 99% yield obtained within 18 h compared to 48% of ENP hydrolysis observed after 162 h. The combined theoretical and experimental results presented here contribute to the development of potent and robust all-inorganic cluster-based catalysts for the degradation of PEU and PET and suggest that ENP and EGD can be used as excellent model substrates in this endeavor.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 21","pages":"5268–5283 5268–5283"},"PeriodicalIF":2.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating the pH Effects on Oleic Acid and Interactions with Lipid Membranes.","authors":"Dongping Jiang, Yu-Chien Lin, Sungmin Shin, Younghwan Choe, Nam-Joon Cho","doi":"10.1021/acs.jpcb.5c00994","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c00994","url":null,"abstract":"<p><p>The interplay between fatty acids (FAs) and lipid membranes under varying pH conditions is important for deciphering fundamental cellular processes and advancing the design of responsive applications. Endowed with membrane incorporation, fatty acids (FAs) can induce curvature on membranes, resulting in alterations in fluidity, permeability, and stability. Despite the wide amount of research on membrane effects induced by FAs, the pH effect on their interaction behaviors remained unclear. Considering the varying pH environments in vivo, the study investigates how pH modulates the aggregation behavior of oleic acid (OA) and its subsequent interactions with lipid membranes. First, the critical aggregation concentration (CAC) was measured to determine the condition when aggregates formed. Less ordered aggregates with a lower zeta potential were observed under elevated pH conditions. These aggregates were further introduced to lipid membranes to evaluate the corresponding membrane responses using a QCM-D and fluorescence microscopy. pH shifts dramatically alter the OA protonation states of their headgroups, driving their insertion, orientation, and aggregation within membranes. Specifically, under lower pH levels, OA demonstrated an incorporation behavior into the membrane structure with increased membrane viscoelasticity, while disturbance of membrane structural integrity was observed under elevated pH levels. A transition from flatter budding protrusions to elongated tubes on the membrane was observed for incorporated OA, primarily owing to the increasing deprotonation degree that resulted in a change in the packing parameter. A stronger impact on cell viability at higher pH levels verified the membrane disruption behaviors. These findings elucidated that the protonation states of OA headgroups critically influence their membrane affinity and packing behavior, offering new perspectives for understanding membrane biophysics and designing pH-responsive delivery systems.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational and Experimental Study of the Conformational Variation of the Catalytic Residue His41 of the SARS-CoV-2 Main Protease","authors":"Jiao Zhou,&nbsp;Xiang Liu,&nbsp;Yan Xu,&nbsp;Juan Wang,&nbsp;Tingli Qian,&nbsp;Xiaohong Sang,&nbsp;Md Nazmul Hasan,&nbsp;Arieh Warshel,&nbsp;Jing An*,&nbsp;Arjun Saha* and Ziwei Huang*,&nbsp;","doi":"10.1021/acs.jpcb.5c0171810.1021/acs.jpcb.5c01718","DOIUrl":"https://doi.org/10.1021/acs.jpcb.5c01718https://doi.org/10.1021/acs.jpcb.5c01718","url":null,"abstract":"<p >The main protease (M^pro) is essential for the replication of SARS-CoV-2, making it one of the major therapeutic targets for COVID-19 treatment. Here, we explored the conformational dynamics and energetics of the catalytic residue His41 in M^pro, as revealed by a rare conformational shift observed in the cocrystal structures of M^pro bound by certain inhibitors. Using steered molecular dynamics combined with umbrella sampling, we demonstrated that π–cation interactions between these inhibitors and the ionized catalytic dyad significantly reduced the energy barrier for the conformational flip of the His41 side chain. To further investigate the structure–activity relationship linked to this conformational change, we designed and synthesized a series of covalent inhibitors that control His41 flipping. Among these, compound H102-7 exhibited remarkable inhibitory activity with an IC₅₀ of 5 nM. Drug resistance studies revealed that these inhibitors displayed improved resistance profiles compared to the clinically approved M^pro covalent inhibitor, Nirmatrelvir. This study integrates computational simulations, medicinal chemistry, and molecular biology to uncover an interesting allosteric effect of a key catalytic residue of SARS-CoV-2 M^pro and yields new promising molecules for the further development of M^pro-targeted therapeutic intervention.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":"129 21","pages":"5198–5206 5198–5206"},"PeriodicalIF":2.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}