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An atomic-scale mechanism of T Cell Receptor (TCR) mechanosensing of peptides in the binding groove of the peptide-major histocompatibility complex (pMHC) may inform the design of novel TCRs for immunotherapies. Using steered molecular dynamics simulations, our study demonstrates that mutations to peptides in the binding groove of the pMHC - which are known to discretely alter the T cell response to an antigen - alter the MHC conformation at equilibrium. This subsequently impacts the overall strength (duration and length) of the TCR-pMHC bond under constant load. Moreover, physiochemical features of the TCR-pMHC dynamic bond strength, such as hydrogen bonds and Lennard-Jones contacts, correlate with the immunogenic response elicited by the specific peptide in the MHC groove. Thus, formation of transient TCR-pMHC bonds is characteristic of immunogenic peptides, and steered molecular dynamics simulations can be used in the overall design strategy of TCRs for immunotherapies.

Proteins undergo a series of conformational changes when affected by the applied electric field, which changes their functions and properties. The conformational changes in proteins in various electric fields are different due to their internal structures. This study simulates the molecular dynamics of proteins in different amounts and directions of electric fields with gromacs software. According to the root mean square deviation, hydrogen bond, dipole moment, and solvent accessible surface area, it is proved that the conformation change in proteins is more drastic under the simultaneous action of multiple electric fields under various directions, and different fragments unfold with divergent electric fields combined, which is of great importance to control protein function, improve biochemical research and production efficiency in the food and drug safety field. [ABSTRACT FROM AUTHOR]

The aggregation structure of Triton X (TX) amphiphilic molecules in aqueous solution plays an important role in determining the various properties and applications of surfactant solutions. In this paper, the properties of micelles formed by TX-5, TX-114, and TX-100 molecules with different poly(ethylene oxide) (PEO) chain lengths in TX series of nonionic surfactants were studied via molecular dynamics (MD) simulation. The structural characteristics of three micelles were analyzed at the molecular level, including the shape and size of micelles, the solvent accessible surface area, the radial distribution function, the micelle configuration, and the hydration numbers. With the increase of PEO chain length, the micelle size and solvent accessible surface area also increase. The distribution probability of the polar head oxygen atoms on the surface of the TX-100 micelle is higher than that in the TX-5 or TX-114 micelle. In particular, the tail quaternary carbon atoms in the hydrophobic region are mainly located at the micelle exterior. For TX-5, TX-114, and TX-100 micelles, the interactions between micelles and water molecules are also quite different. These structures and comparisons at the molecular level contribute to the further understanding of the aggregation and applications of TX series surfactants. [ABSTRACT FROM AUTHOR]

Proteins undergo a series of conformational changes when affected by the applied electric field, which changes their functions and properties. The conformational changes in proteins in various electric fields are different due to their internal structures. This study simulates the molecular dynamics of proteins in different amounts and directions of electric fields with gromacs software. According to the root mean square deviation, hydrogen bond, dipole moment, and solvent accessible surface area, it is proved that the conformation change in proteins is more drastic under the simultaneous action of multiple electric fields under various directions, and different fragments unfold with divergent electric fields combined, which is of great importance to control protein function, improve biochemical research and production efficiency in the food and drug safety field.

Protein structure holds immense potential for pathogenicity prediction, albeit structure-based predictors are limited compared to the sequence-based counterparts due to the "structure knowledge gap" between large number of available protein sequences and relatively limited number of structures. Leveraging the highly accurate protein structures predicted by AlphaFold2 (AF2), we introduce AFFIPred, an ensemble machine learning classifier that combines sequence and AF2-based structural characteristics to predict missense variant pathogenicity. Based on the assessments on unseen datasets, AFFIPred reached a comparable level of performance with the state-of-the-art predictors such as AlphaMissense. We also showed that the recruitment of AF2 structures that are full-length and represent the unbound states ensures more precise SASA calculations compared to the recruitment of experimental structures. In line with the completeness of the AF2 structures, their use provide a more comprehensive view of the structural characteristics of the missense variation datasets by capturing all variants. AFFIPred maintains high-level accuracy without the limitations of PDB-based classifiers. AFFIPred has predicted over 210 million variations of the human proteome, which are accessible at https://affipred.timucinlab.com/., (© 2025 The Protein Society.)

Pour point, or the temperature below which a fluid ceases to flow, is an important lubricant property. A molecular-dynamics-based approach is developed to explore and identify the pour points of a number of fluids. Diffusion behaviors of several fluids are investigated by time-averaged mean squared displacement (MSD), and a clear trend change of the MSD data is observed as a function of temperature. The temperature at this trend change corresponds well with the experimental pour point. Further, a correlation formula is obtained to link pour point and the ratio of the solvent accessible surface area (SASA), which is defined as the locus surface of the center of a solvent probe when it rolls over the surface of the fluid molecule, to the total number of carbon, in terms of SASA/Nc, and several molecular structural features. The pour points obtained from the molecular dynamics (MD) simulation and formula prediction are compared with existing experimental results, and the good agreement supports the proposed pour-point determination methods. [ABSTRACT FROM AUTHOR]

We are introducing Pep McConst—a software that employs a Monte‐Carlo algorithm to construct 3D structures of polypeptide chains which could subsequently be studied as stand‐alone macromolecules or complement the structure of known proteins. Using an approach to avoid steric clashes, Pep McConst allows to create multiple structures for a predefined primary sequence of amino acids. These structures could then effectively be used for further structural analysis and investigations. The article introduces the algorithm and describes its user‐friendly approach that was made possible through the VIKING online platform. Finally, the manuscript provides several highlight examples where Pep McConst was used to predict the structure of the C‐terminal of a known protein, generate a missing bit of already crystallized protein structures and simply generate short polypeptide chains. [ABSTRACT FROM AUTHOR]

Solvent accessibility (SASA) is a key feature of proteins for determining their folding and stability. SASA is computed from protein structures with different algorithms, and from protein sequences with machine-learning based approaches trained on solved structures. Here we ask the question as to which extent solvent exposure of residues can be associated to the pathogenicity of the variation. By this, SASA of the wild-type residue acquires a role in the context of functional annotation of protein single-residue variations (SRVs). By mapping variations on a curated database of human protein structures, we found that residues targeted by disease related SRVs are less accessible to solvent than residues involved in polymorphisms. The disease association is not evenly distributed among the different residue types: SRVs targeting glycine, tryptophan, tyrosine, and cysteine are more frequently disease associated than others. For all residues, the proportion of disease related SRVs largely increases when the wild-type residue is buried and decreases when it is exposed. The extent of the increase depends on the residue type. With the aid of an in house developed predictor, based on a deep learning procedure and performing at the state-of-the-art, we are able to confirm the above tendency by analyzing a large data set of residues subjected to variations and occurring in some 12,494 human protein sequences still lacking three-dimensional structure (derived from HUMSAVAR). Our data support the notion that surface accessible area is a distinguished property of residues that undergo variation and that pathogenicity is more frequently associated to the buried property than to the exposed one.

Knowledge of three-dimensional protein structure is integral to most modern drug discovery efforts. Recent advancements have highlighted new techniques for 3D protein structure determination and, where structural data cannot be collected experimentally, prediction of protein structure. We have undertaken a major effort to use existing protein structures to collect, characterize, and catalogue the inter-atomic interactions that define and compose 3D structure by mapping hydropathic interaction environments as maps in 3D space. This work has been performed on a residue-by-residue basis, where we have seen evidence for relationships between environment character, residue solvent-accessible surface areas and their secondary structures. In this graphical review, we apply principles from our earlier studies and expand the scope to all common amino acid residue types in both soluble and membrane proteins. Key to this analysis is parsing the Ramachandran plot to an 8-by-8 chessboard to define secondary structure bins. Our analysis yielded a number of quantitative discoveries: 1) increased fraction of hydrophobic residues (alanine, isoleucine, leucine, phenylalanine and valine) in membrane proteins compared to their fractions in soluble proteins; 2) less burial coupled with significant increases in favorable hydrophobic interactions for hydrophobic residues in membrane proteins compared to soluble proteins; and 3) higher burial and more favorable polar interactions for polar residues now preferring the interior of membrane proteins. These observations and the supporting data should provide benchmarks for current studies of protein residues in different environments and may be able to guide future protein structure prediction efforts.

Abstract Hospital‐acquired infection causes many deaths worldwide and calls for the urgent need for antibacterial biomaterials used in clinic that can selectively kill harmful bacteria. The present study rationally designs fusion peptides capable of undergoing 2D self‐assembly on the poly(methyl methacrylate) surface to form a smart surface, which can maintain a desirable orientation via electrostatic interactions. The in vitro assay shows that the smart surface can recognize bacteria to exert antibacterial activity and is nontoxic toward mouse bone mesenchymal stem cells. Excitingly, the smart surface can distinguish different bacterial strains. This selective feature, from being broad‐spectrum to being highly selective against S. aureus, can be altered by varying the number of amino acids in the recognition sequences. By all‐atom molecular dynamics simulations, it is also found that the recognition sequence in the peptide is critical for the selectivity toward specific bacterial strains, in which a less accessible surface area for the bacteria in the antimicrobial peptide sequence is responsible for such selectivity. Finally, the smart surface can inhibit S. aureus infection in vivo with much more rapid tissue‐healing compared to the control.

Over wide temperature and pressure ranges, the molecular dynamics simulation is performed to study the mass transfer of six n-alkanes from n-C5H12 to n-C10H22 in CO2 at infinite dilution by calculating the diffusion coefficients, which have not yet been measured by experiment. Meanwhile, the structural properties of these systems are explored. It is found that under different temperature and pressure conditions, the variation trends of the radial distribution functions of n-alkanes are quite different, while the variation trends of the average coordination number of n-alkanes can be divided into three types. The radius of gyration and the solvent accessible surface area are both affected by temperature and carbon chain length, but their variation trends are different, and it could explain the abnormal variation trends of the radial distribution functions and the average coordination number. [ABSTRACT FROM AUTHOR]

The heat capacity change, ΔCp, accompanying the folding/unfolding of macromolecules reflects their changing state of hydration. Thermal denaturation of the DNA duplex is characterized by an increase in ΔCp but of much lower magnitude than observed for proteins. To understand this difference, the changes in solvent accessible surface area (ΔASA) have been determined for unfolding the B-form DNA duplex into disordered single strands. These showed that the polar component represents ~ 55% of the total increase in ASA, in contrast to globular proteins of similar molecular weight for which the polar component is only about 1/3rd of the total. As the exposure of polar surface results in a decrease of ΔCp, this explains the much reduced heat capacity increase observed for DNA and emphasizes the enhanced role of polar interactions in maintaining duplex structure. Appreciation of a non-zero ΔCp for DNA has important consequences for the calculation of duplex melting temperatures (Tm). A modified approach to Tm prediction is required and comparison is made of current methods with an alternative protocol. [ABSTRACT FROM AUTHOR]

All R s values become larger with adsorbed counterions, however, organic counterions adsorbed onto micelles can decrease the SASA, which is contrary to the inorganic Cl− ions. [Display omitted] • Absorbed PO− and BZ− ions lead to the decrease in SASA. • The Cl− ions are adsorbed on micelle surface while PO− and BZ− ions penetrate deeper into the micellar interior. • Water molecules penetrate into the deepest position in [C 14 mim][Cl] micelle. Self-assembly of ionic liquids (ILs) in solution has attracted wide attention due to their potential applications in various fields. The nature of counterions, especially aromatic counterions, will significantly affect the aggregation and morphological properties of ILs surfactants. In this paper, molecular dynamics (MD) simulations are applied to study the influence of three organic and inorganic counterions (phenolate (PO−), benzoate (BZ−), and Cl−) on the micellar structure of imidazolium (C 14 mim+) based ILs surfactant in aqueous solutions. Three micelles all possess prolate shape. The PO−, BZ−, and Cl− ions hardly affect the orientation and length of hydrophobic chains in micellar interior. Hydration numbers and average radial density distributions analyses show that interactions between micelles and water molecules are different in studied micelles. Surrounding water molecules penetrate into the deepest region in [C 14 mim][Cl] micelle. However, adsorbed Cl− ions are mainly located on micellar surface, not penetrating into micellar interior. Due to the intrinsic hydrophobicity of organic ions, both PO− and BZ− ions enter into deeper positions in micelles. Unlike Cl− ions, there exist π-interactions between adsorbed PO− and BZ− ions themselves. One interesting finding is that adsorbed PO− and BZ− ions can make micelle radius (R g) increase but make solvent accessible surface area (SASA) decrease. Conversely, adsorbed Cl− ions make both R g and SASA increase. Three MD models for different C 14 mim+ based micelles are proposed. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (mAbs) are active components of therapeutic formulations that interact with the water-vapor interface during manufacturing, storage, and administration. Surface adsorption has been demonstrated to mediate antibody aggregation, which leads to a loss of therapeutic efficacy. Controlling mAb adsorption at interfaces requires a deep understanding of the microscopic processes that lead to adsorption and identification of the protein regions that drive mAb surface activity. Here, we report all-atom molecular dynamics (MD) simulations of the adsorption behavior of a full IgG1-type antibody at the water/vapor interface. We demonstrate that small local changes in the protein structure play a crucial role in promoting adsorption. Also, interfacial adsorption triggers structural changes in the antibody, potentially contributing to the further enhancement of surface activity. Moreover, we identify key amino acid sequences that determine the adsorption of antibodies at the water-air interface and outline strategies to control the surface activity of these important therapeutic proteins.

Starting with the Rayleigh charge limiting model, a slightly different approach is used to account for the well-known discrepancy that exists between the said model and experimental ESI MS data for globular proteins. It is shown using published datasets that for globular proteins, the mass density ρ exhibits a weak second-order dependence on its mass M, according to ρ(M)∝M-α, α ~ 0.14. A direct equivalence established between ESI MS and x-ray techniques suggests a minimum but critical surface tension of 15.6 ± 5.2 mN/m for the droplet at the liquid-to-gas phase transition point. The packing density factor η for globular proteins is believed to lie between 1 (very tightly packed) and 4.6 (less tight, natively packed). While the Rayleigh charge limiting model has been linked historically to the CRM (J. Chem. Phys. 49:2240-2249, 1968; Anal. Chim. Acta 406:93-104, 2000), this paper does not expressly seek to justify the CRM, but rather uses empirical data and existing knowledge across subfields to help build a consistent picture of ESI MS phenomena that might be difficult to explain otherwise. These results would be useful in molecular dynamics (MD) simulations, understanding liquid-to-gas phase transitions and in opening up new routes for cross-calibration between ESI MS, IM MS, NMR and x-ray crystallography studies.ᅟ [ABSTRACT FROM AUTHOR]

Fibrillar collagens are the most abundant proteins in the extracellular matrix. Not only do they provide structural integrity to all of the connective tissues in the human body, but also their interactions with multiple cell receptors and other matrix molecules are essential to cell functions, such as growth, repair, and cell adhesion. Although specific binding sequences of several receptors have been determined along the collagen monomer, processes by which collagen binding partners recognize their binding sites in the collagen fibril, and the critical driving interactions, are poorly understood. The complex molecular assembly of bundled triple helices within the collagen fibril makes essential ligand binding sites cryptic or hidden from the molecular surface. Yet, critical biological processes that require collagen ligands to have access to interaction sites still occur. In this contribution, we will discuss the molecular packing of the collagen I fibril from the perspective of how collagen ligands access their known binding regions within the fibril, and we will present our analysis of binding site accessibility from the fibril surface. Understanding the basis of these interactions at the atomic level sets the stage for developing drug targets against debilitating collagen diseases and using collagen as drug delivery systems and new biomaterials. [ABSTRACT FROM AUTHOR]

A systematic investigation of influence of the length of the side alkyl chain and the counter-ions on the thermodynamics of the micellization process at imidazolium based surface active ionic liquids (SAILs) in aqueous solutions was carried out by isothermal titration calorimetry (ITC) in a broad temperature range. The effect of alkyl chain length on the micellization process in water has been investigated on 1-decyl-3-methylimidazolium ([C 10 mim]Cl), 1-dodecyl-3-methylimidazolium ([C 12 mim]Cl), 1- tetradecyl-3-methylimidazolium ([C 14 mim]Cl) and 1-hexadecyl-3- methylimidazolium ([C 16 mim]Cl) chlorides, whereas the influence of counter-ion was studied at the micellization of 1-dodecyl-3-methylimidazolium chloride ([C 12 mim]Cl), bromide ([C 12 mim]Br), iodide ([C 12 mim]I), acetate ([C 12 mim]OAc), methanesulfonate ([C 12 mim]OMs), toluen sulfonate ([C 12 mim]OTs), trifluromethane sulfonate ([C 12 mim]OTf), trifluoro acetate ([C 12 mim]TFA) and salicylate ([C 12 mim]Sal) in water. From ITC experimental data, the corresponding standard thermodynamic parameters of micellization (enthalpy, Δ M H 0 ; Gibbs free energy, Δ M G 0 ; entropy, Δ M S 0 ; heat capacity change, Δ M c p 0 ) were estimated by help of the mass-action model. It was found that SAILs behave mainly like common cationic surfactants, where cmc values are decreasing with the length of the side alkyl chain and exhibit U-shape dependence on temperature. Remarkable influence of counter-ions on cmc and all thermodynamic functions was observed, however the entropy-enthalpy compensation turned out as a matter of fact, arising from the relationship Δ G = Δ H − T Δ S . Δ M c p 0 values were further discussed in terms of the removal of solvent accessible surface areas of SAILs and counter-ion from the contact with water after micellization. [ABSTRACT FROM AUTHOR]

Using fully atomistic molecular dynamics simulation that are several hundred nanoseconds long, we demonstrate the pH-controlled sponge action of PAMAM dendrimer. We show how at varying pH levels, the PAMAM dendrimer acts as a wet sponge; at neutral or low pH levels, the dendrimer expands noticeably and the interior of the dendrimer opens up to host several hundreds to thousands of water molecules depending on the generation number. Increasing the pH (i.e., going from low pH to high pH) leads to the collapse of the dendrimer size, thereby expelling the inner water, which mimics the 'sponge' action. As the dendrimer size swells up at a neutral pH or low pH due to the electrostatic repulsion between the primary and tertiary amines that are protonated at this pH, there is dramatic increase in the available solvent accessible surface area (SASA), as well as solvent accessible volume (SAV). [ABSTRACT FROM AUTHOR]

We investigate the effects of protein crowder sizes on hydration structure and dynamics in macromolecular crowded systems by all-atom MD simulations. The crowded systems consisting of only small proteins showed larger total surface areas than those of large proteins at the same volume fractions. As a result, more water molecules were trapped within the hydration shells, slowing down water diffusion. The simulation results suggest that the protein crowder size is another factor to determine the effect of macromolecular crowding and to explain the experimental kinetic data of proteins and DNAs in the presence of crowding agents. [ABSTRACT FROM AUTHOR]

Calculating solvent accessible surface areas (SASA) is a run-of-the-mill calculation in structural biology. Although there are many programs available for this calculation, there are no free-standing, open-source tools designed for easy tool-chain integration. FreeSASA is an open source C library for SASA calculations that provides both command-line and Python interfaces in addition to its C API. The library implements both Lee and Richards’ and Shrake and Rupley’s approximations, and is highly configurable to allow the user to control molecular parameters, accuracy and output granularity. It only depends on standard C libraries and should therefore be easy to compile and install on any platform. The library is well-documented, stable and efficient. The command-line interface can easily replace closed source legacy programs, with comparable or better accuracy and speed, and with some added functionality.

We characterise the hydrophobic collapse of single polystyrene chains in water using molecular dynamics simulations. Specifically, we calculate the potential of mean force for the collapse of a single polystyrene chain in water using metadynamics, comparing the results between all atomistic with coarse-grained (CG) molecular simulation. We next explore the scaling behaviour of the collapsed globular shape at the minimum energy configuration, characterised by the radius of gyration, as a function of chain length. The exponent is close to one third, consistent with that predicted for a polymer chain in bad solvent. We also explore the scaling behaviour of the solvent accessible surface area (SASA) as a function of chain length, finding a similar exponent for both all atomistic and CG simulations. Furthermore, calculation of the local water density as a function of chain length near the minimum energy configuration suggests that intermediate chain lengths are more likely to form dewetted states, as compared to shorter or longer chain lengths. [ABSTRACT FROM AUTHOR]

Cultivation of mammalian cells for the generation of therapeutics requires the use of cell culture media which is a defined mixture of nutrients including carbohydrates, amino acids, lipids, vitamins, and inorganic salts. Its composition influences the cell density, yield, and quality of the molecule expressed. These chemically defined cell culture media are manufactured as powders since they offer advantages of storage, handling and stability. To prevent de-mixing of the powders and maintain homogeneity, these powders are milled down to small particle size ranges. However, this small particle size allows for inter-particle forces to impact powder flow properties, and decreases the surface area available to dissolution. Hence a method is required that improves these powder parameters, without altering their composition. A deeper understanding of the dissolution mechanism of multi-component mixtures like cell culture media is also needed. Here, cell culture media granules, generated from homogeneous powders by roller compaction are evaluated. The granulation process did not alter the composition of the media and properties of solutions generated thereof. The analysis and comparison of the dissolution profile of powder and compacted media enabled the calculation of the actual surface area available to dissolution. The improvement in granule dissolution can be attributed to dispersion and disintegration of the granules on wetting increasing available surface area. Decrease in inter-particle forces in granules also improves flow-ability properties. Surface character and pores on the granules further augments the improvement in dissolution. [ABSTRACT FROM AUTHOR]

In this study, we estimated the optimum concentration of copper ions that are effective in the stability and the structural changes of human growth hormone (hGH) protein in the combination of different concentrations of these ions at the molecular level using molecular dynamics simulation by Gromacs 4.6.5 software. Moreover, to estimate the binding affinity of copper ions to hGH protein, binding free energies is calculated by the molecular mechanics Poisson-Boltzmann Surface Area (MM-PBSA). The analysis of molecular dynamics (MD) trajectories as dictionary of the secondary structure of protein (DSSP), solvent accessible surface area (SASA) and binding free energy calculations show that hGH protein structure is more stabilized by increasing a limited concentration of copper ions. These findings align with our previous experimental studies. [ABSTRACT FROM AUTHOR]

The singlet oxygen quenching rate constants were measured for three model proteins, bovine serum albumin, β-lactoglobulin and lysozyme. The results were analyzed by comparing them with the corresponding singlet oxygen quenching rate constants for a series of tripeptides with the basic formula GlyAAGly where the central amino acid (AA) was the oxidizable amino acid, tryptophan, tyrosine, methionine and histidine. It was found that the reaction rate constant in proteins can be satisfactorily modelled by the sum of the individual contributions of the oxidizable AA residues corrected for the solvent accessible surface area (SASA) effects. The best results were obtained when the SASA of the AA residues were determined by averaging over molecular dynamics simulated trajectories of the proteins. The limits of this geometrical correction of the AA residue reactivity are also discussed. [ABSTRACT FROM AUTHOR]

The coupling of chromatography with mass spectrometry (MS) has becoming a routine technique in proteomics for protein primary sequence and post translational modification determinations. Up to date, great efforts have been made to extend its capability to probe protein higherorder structures (HOS) in the hope of achieving high-throughput protein structure analysis in complex samples. With complementary analytical capabilities, the coupling of native capillary electrophoresis and mass spectrometry (CE-MS) emerges as a promising approach for intact protein and protein complex conformation investigations. This review summarizes recent native CE-MS advances in two aspects: 1. native CE-MS for separation and differentiation of proteoforms; 2. native CE-MS methodology developments for protein HOS related parameter measurements, including protein effective charge, solvent accessible surface area, protein-ligand binding constant, 3D shape and dimensions. In this review, we focus on native CE-MS works with an emphasize on protein HOS information acquisition, and the developments of CE-MS interfaces or methods for top-down proteomics were not covered, which has been well summarized in literature. • In this review, we have discussed recent advances on CE MS for probing protein HOSs in native conditions. • Advances in instrumentation enabled high throughput proteoform analyses and growing numbers of proterforms being identified. • Besides proteoforms, CE-nMS methods were also developed to extract protein HOS related structural parameters. • Methodology developments helped CE-MS to obtain structural information and expands its application in structural biology. [ABSTRACT FROM AUTHOR]