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1.
Sci Data ; 11(1): 180, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336857

RESUMO

Computing binding affinities is of great importance in drug discovery pipeline and its prediction using advanced machine learning methods still remains a major challenge as the existing datasets and models do not consider the dynamic features of protein-ligand interactions. To this end, we have developed PLAS-20k dataset, an extension of previously developed PLAS-5k, with 97,500 independent simulations on a total of 19,500 different protein-ligand complexes. Our results show good correlation with the available experimental values, performing better than docking scores. This holds true even for a subset of ligands that follows Lipinski's rule, and for diverse clusters of complex structures, thereby highlighting the importance of PLAS-20k dataset in developing new ML models. Along with this, our dataset is also beneficial in classifying strong and weak binders compared to docking. Further, OnionNet model has been retrained on PLAS-20k dataset and is provided as a baseline for the prediction of binding affinities. We believe that large-scale MD-based datasets along with trajectories will form new synergy, paving the way for accelerating drug discovery.


Assuntos
Ligantes , Proteínas , Descoberta de Drogas , Aprendizado de Máquina , Ligação Proteica , Proteínas/química , Humanos , Animais
2.
J Chem Phys ; 160(1)2024 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-38165098

RESUMO

Understanding the influence of a crowded intracellular environment on the structure and solvation of DNA functionalized gold nanoparticles (ss-DNA AuNP) is necessary for designing applications in nanomedicine. In this study, the effect of single (Gly, Ser, Lys) and mixture of amino acids (Gly+Ser, Gly+Lys, Ser+Lys) at crowded concentrations is examined on the structure of the ss-DNA AuNP using molecular dynamics simulations. Using the structural estimators such as pair correlation functions and ligand shell positional fluctuations, the solvation entropy is estimated. Combining the AuNP-solvent interaction energy with the solvation entropy estimates, the free energy of solvation of the AuNP in crowded solutions is computed. The solvation entropy favours the solvation free energy which becomes more favourable for larger effective size of AuNP in crowded solutions relative to that in water. The effective size of AuNP depends on the different propensity of the crowders to adsorb on Au surface, with the smallest crowder (Gly) having the highest propensity inducing the least effective AuNP size as compared to other single crowder solutions. In mixed crowded solutions of amino acids of variable size and chemistry, distinctive local adsorption of the crowders on the gold surface is observed that controls the additive or non-additive crowding effects which govern an increase (in Gly+Ser) or decrease (in Gly+Lys) in nanoparticle effective size respectively. The results shed light into the fundamental understanding of the influence of intracellular crowding on structure of ss-DNA AuNP and plausible employability of crowding as a tool to design programmable self-assembly of functionalized nanoparticles.


Assuntos
Ouro , Nanopartículas Metálicas , Ouro/química , Nanopartículas Metálicas/química , DNA/química , Entropia , Aminoácidos
3.
Angiology ; : 33197231225282, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38173053

RESUMO

COronaVIrus Disease-2019 (COVID-19) is associated with a hypercoagulable state. Intracardiac thrombosis is a potentially serious complication but has seldom been evaluated in COVID-19 patients. We assessed the incidence, associated factors, and outcomes of COVID-19 patients with intracardiac thrombosis. In 2020, COVID-19 inpatients were identified from the National Inpatient Sample (NIS) database. Data on clinical characteristics, intracardiac thrombosis, and adverse outcomes were collected. Multivariable logistic regression was used to identify factors associated with intracardiac thrombosis, in-hospital mortality, and morbidities. In 2020, 1,683,785 COVID-19 inpatients (mean age 63.8 years, 32.2% females) were studied. Intracardiac thrombosis occurred in 0.10% (1830) of cases. In-hospital outcomes included 13.2% all-cause mortality, 3.5% cardiovascular mortality, 2.6% cardiac arrest, 4.4% acute coronary syndrome (ACS), 16.1% heart failure, 1.3% stroke, and 28.3% acute kidney injury (AKI). Key factors for intracardiac thrombosis were congestive heart failure history and coagulopathy. Intracardiac thrombosis independently linked to higher risks of all-cause mortality (odds ratio [OR]: 3.32 (2.42-4.54)), cardiovascular mortality (OR: 2.95 (1.96-4.44)), cardiac arrest (OR: 2.04 (1.22-3.43)), ACS (OR: 1.62 (1.17-2.22)), stroke (OR: 3.10 (2.11-4.56)), and AKI (OR: 2.13 (1.68-2.69)), but not heart failure. While rare, intracardiac thrombosis in COVID-19 patients independently raised in-hospital mortality and morbidity risks.

4.
Acad Radiol ; 31(4): 1256-1261, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37802673

RESUMO

Radiology has always gone hand-in-hand with technology and artificial intelligence (AI) is not new to the field. While various AI devices and algorithms have already been integrated in the daily clinical practice of radiology, with applications ranging from scheduling patient appointments to detecting and diagnosing certain clinical conditions on imaging, the use of natural language processing and large language model based software have been in discussion for a long time. Algorithms like ChatGPT can help in improving patient outcomes, increasing the efficiency of radiology interpretation, and aiding in the overall workflow of radiologists and here we discuss some of its potential applications.


Assuntos
Inteligência Artificial , Radiologia , Humanos , Radiografia , Radiologistas , Algoritmos
5.
J Kidney Cancer VHL ; 10(3): 23-31, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37555195

RESUMO

Von Hippel-Lindau disease (VHL) is a multisystem cancer syndrome caused by the inactivation of the VHL tumor suppressor gene and involves various organ systems including the central nervous system (CNS), endocrine system, and the kidneys. Tumors seen in patients with VHL disease can be benign or malignant and are usually multifocal, bilateral, and hypervascular in nature. As most lesions associated with VHL are asymptomatic initially, early diagnosis and the institution of an evidence-based surveillance protocol are of paramount importance. Screening, surveillance, and genetic counseling are key aspects in the management of patients diagnosed with VHL disease and often require a multidisciplinary approach and referral to specialized centers. This article will discuss the characteristic lesions seen with VHL disease, their diagnosis, screening protocols and management strategies, as well as an illustrative case to demonstrate the natural progression of the disease with classic imaging findings.

6.
Soft Matter ; 19(33): 6399-6413, 2023 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-37580997

RESUMO

The intriguing role of the intracellular crowded environment in regulating protein aggregation remains elusive. The convolution of several factors such as the protein sequence-dependence, crowder's shape and size and diverse intermolecular interactions makes it complex to identify systematic trends. One of the ways to simplify the problem is to study a synthetic model for self-assembling proteins. In this study, we examine the aggregation behaviour of the cationic pseudoisocyanine chloride (PIC) dyestuff which is known to self-assemble and form fibril-like J-aggregates in aqueous solutions, similar to those formed by amyloid-forming proteins. Prior experimental studies have shown that polyethylene glycol impedes and Ficoll-400 promotes the self-assembly of PIC dyes. To achieve molecular insights, we examine the effect of crowding by ethylene glycol on the solvation thermodynamics of oligomerization of dyes into H-type and J-type oligomers using extensive molecular dynamics simulations. The binding free energy calculations show that the formation of J-oligomers is more favourable than that of H-oligomers in water. The stability of H- and J- tetramers and pentamers decreases in crowded solutions. The formation of oligomers is supported by the favourable change in dye-solvent interaction energy in both pure water and aqueous ethylene glycol solution although it is opposed by the reduced dye-solvent entropy. Ethylene glycol, as a molecular crowder, disfavours the H- as well as J-oligomerization via preferential binding to the dye oligomers. An unfavourable change in dye-crowder and dye-dye interaction energy on dye association makes the H-oligomer formation less favourable in crowded solution than in pure water solution. In the case of J-oligomers, however, the unfavourable change in dye-crowder interaction energy primarily contributes to making total dye-solvent energy unfavourable. The results are supported by isothermal titration calorimetry measurements where the binding of ethylene glycol to PIC molecules is found to be endothermic. The results provide an emerging view that a crowded environment can disfavour self-assembly of PIC dyes by interactions with the oligomeric states. The findings have implications in understanding the role of a crowded environment in shaping the free energy landscapes of proteins.


Assuntos
Corantes , Etilenoglicol , Água/química , Solventes
7.
Neuroradiol J ; : 19714009231196476, 2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37608426

RESUMO

Malignant Triton Tumors (MTTs) are a rare and aggressive subtype of malignant peripheral nerve sheath tumors (MPNSTs), often associated with neurofibromatosis type 1. This case report describes a unique instance of recurrent sporadic MTT within the carotid sheath in a 33-year-old male without any personal or familial history of neurofibromatosis. The patient initially presented with a biopsy-confirmed MTT in the right neck, involving the carotid body and brachial plexus, and underwent partial resection, radiation therapy, and chemotherapy. Six months later, the patient presented with recurrent MTT, and subsequently underwent radical tumor resection, segmental right carotid artery resection, and deep femoral vein interposition. Recovery was complicated by hematoma formation, and the patient developed vocal fold paralysis and a left vocal fold cyst, necessitating further surgeries. Yearly follow-ups for 8 years revealed no recurrence. This case emphasizes the importance of comprehensive patient evaluation, including clinical history, imaging, and biopsy findings, for accurate diagnosis and prompt surgical intervention in managing such rare and aggressive tumors. Further research is needed to identify novel therapies and improve survival rates for patients with MTTs.

8.
J Phys Chem B ; 127(28): 6265-6276, 2023 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-37410958

RESUMO

A comprehensive understanding of protein folding and biomolecular self-assembly in the intracellular environment requires obtaining a microscopic view of the crowding effects. The classical view of crowding explains biomolecular collapse in such an environment in terms of the entropic solvent excluded volume effects subjected to hard-core repulsions exerted by the inert crowders, neglecting their soft chemical interactions. In this study, the effects of nonspecific, soft interactions of molecular crowders in regulating the conformational equilibrium of hydrophilic (charged) polymers are examined. Using advanced molecular dynamics simulations, collapse free energies of an uncharged, a negatively charged, and a charge-neutral 32-mer generic polymer are computed. The strength of the polymer-crowder dispersion energy is modulated to examine its effect on polymer collapse. The results show that the crowders preferentially adsorb and drive the collapse of all three polymers. The uncharged polymer collapse is opposed by the change in solute-solvent interaction energy but is overcompensated by the favorable change in the solute-solvent entropy as observed in hydrophobic collapse. However, the negatively charged polymer collapses with a favorable change in solute-solvent interaction energy due to reduction in the dehydration energy penalty as the crowders partition to the polymer interface and shield the charged beads. The collapse of a charge-neutral polymer is opposed by the solute-solvent interaction energy but is overcompensated by the solute-solvent entropy change. However, for the strongly interacting crowders, the overall energetic penalty decreases since the crowders interact with polymer beads via cohesive bridging attractions to induce polymer collapse. These bridging attractions are found to be sensitive to the binding sites of the polymer, since they are absent in the negatively charged or uncharged polymers. These interesting differences in thermodynamic driving forces highlight the crucial role of the chemical nature of the macromolecule as well as of the crowder in determining the conformational equilibria in a crowded milieu. The results emphasize that the chemical interactions of the crowders should be explicitly considered to account for the crowding effects. The findings have implications in understanding the crowding effects on the protein free energy landscapes.

9.
Phys Chem Chem Phys ; 25(7): 5430-5442, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36744506

RESUMO

A comprehensive understanding of crowding effects on biomolecular processes necessitates investigating the bulk thermodynamic and kinetic properties of the solutions with an accurate molecular representation of the crowded milieu. Recent studies have reparameterized the non-bonded dispersion interaction of solutes to precisely model intermolecular interactions, which would circumvent artificial aggregation as shown by the original force-fields. However, the performance of this reparameterization is yet to be assessed for concentrated crowded solutions in terms of investigating the hydration shell structure, energetics and dynamics. In this study, we perform molecular dynamics simulations of crowded aqueous solutions of five zwitterionic neutral amino acids (Gly, Ala, Thr, Pro, and Ser), mimicking the molecular crowding environment, using a modified AMBER ff99SB-ILDN force-field. We systematically examine and show that the reproducibility of the osmotic coefficients, density, viscosity and self-diffusivity of amino acids improves using the modified force-field in crowded concentrations. The modified force-field also improves the structuring of the solute solvation shells, solute interaction energy and convergence of tails of radial distribution functions, indicating reduction in the artificial aggregation. Our results also indicate that the hydrogen bonding network of water weakens and water molecules anomalously diffuse at small time scales in the crowded solutions. These results underscore the significance of examining the solution properties and anomalous hydration behaviour of water in crowded solutions, which have implications in shaping the structure and dynamics of biomolecules. The findings also illustrate the improvement in predicting bulk solution properties using the modified force-field, thereby providing an approach towards accurate modeling of crowded molecular solutions.


Assuntos
Aminoácidos , Simulação de Dinâmica Molecular , Aminoácidos/química , Reprodutibilidade dos Testes , Soluções , Água/química
10.
ACS Omega ; 8(2): 2389-2397, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36687059

RESUMO

Drug design involves the process of identifying and designing molecules that bind well to a given receptor. A vital computational component of this process is the protein-ligand interaction scoring functions that evaluate the binding ability of various molecules or ligands with a given protein receptor binding pocket reasonably accurately. With the publicly available protein-ligand binding affinity data sets in both sequential and structural forms, machine learning methods have gained traction as a top choice for developing such scoring functions. While the performance shown by these models is optimistic, there are several hidden biases present in these data sets themselves that affect the utility of such models for practical purposes such as virtual screening. In this work, we use published methods to systematically investigate several such factors or biases present in these data sets. In our analysis, we highlight the importance of considering sequence, protein-ligand interaction, and pocket structure similarity while constructing data splits and provide an explanation for good protein-only and ligand-only performances in some data sets. Through this study, we provide to the community several pointers for the design of binding affinity predictors and data sets for reliable applicability.

11.
Sci Data ; 9(1): 548, 2022 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071074

RESUMO

Computational methods and recently modern machine learning methods have played a key role in structure-based drug design. Though several benchmarking datasets are available for machine learning applications in virtual screening, accurate prediction of binding affinity for a protein-ligand complex remains a major challenge. New datasets that allow for the development of models for predicting binding affinities better than the state-of-the-art scoring functions are important. For the first time, we have developed a dataset, PLAS-5k comprised of 5000 protein-ligand complexes chosen from PDB database. The dataset consists of binding affinities along with energy components like electrostatic, van der Waals, polar and non-polar solvation energy calculated from molecular dynamics simulations using MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. The calculated binding affinities outperformed docking scores and showed a good correlation with the available experimental values. The availability of energy components may enable optimization of desired components during machine learning-based drug design. Further, OnionNet model has been retrained on PLAS-5k dataset and is provided as a baseline for the prediction of binding affinities.


Assuntos
Simulação de Dinâmica Molecular , Proteínas , Animais , Humanos , Ligantes , Aprendizado de Máquina , Ligação Proteica , Proteínas/química
12.
Dalton Trans ; 50(40): 14062-14080, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34549221

RESUMO

Quantum dots (QDs), owing to their single atom-like electronic structure due to quantum confinement, are often referred to as artificial atoms. This unique physical property results in the diverse functions exhibited by QDs. A wide array of applications have been achieved by the surface functionalization of QDs, resulting in exceptional optical, antimicrobial, catalytic, cytotoxic and enzyme inhibition properties. Ordinarily, traditionally prepared QDs are subjected to post synthesis functionalization via a variety of methods, such as ligand exchange or covalent and non-covalent conjugation. Nevertheless, solvent toxicity, combined with the high temperature and pressure conditions during the preparation of QDs and the low product yield due to multiple steps in the functionalization, limit their overall use. This has driven scientists to investigate the development of greener, environmental friendly and cost-effective methods that can circumvent the complexity and strenuousness associated with traditional processes of bio-functionalization. In this review, a detailed analysis of the methods to bio-prepare pre-functionalized QDs, with elucidated mechanisms, and their application in the areas of catalysis and biomedical applications has been conducted. The environmental and health and safety aspects of the bio-derived QDs have been briefly discussed to unveil the future of nano-commercialization.


Assuntos
Pesquisa Biomédica , Pontos Quânticos/química , Catálise
13.
J Chem Phys ; 155(2): 024903, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34266250

RESUMO

Understanding the fundamental forces such as hydrophobic interactions in a crowded intracellular environment is necessary to comprehensively decipher the mechanisms of protein folding and biomolecular self-assemblies. The widely accepted entropic depletion view of crowding effects primarily attributes biomolecular compaction to the solvent excluded volume effects exerted by the "inert" crowders, neglecting their soft interactions with the biomolecule. In this study, we examine the effects of chemical nature and soft attractive energy of crowders on the water-mediated hydrophobic interaction between two non-polar neopentane solutes using molecular dynamics simulations. The crowded environment is modeled using dipeptides composed of polar and non-polar amino acids of varying sizes. The results show that amongst the non-polar crowders, Leu2 strengthens the hydrophobic interactions significantly, whereas the polar and small-sized non-polar crowders do not show significant strengthening. Distinct underlying thermodynamic driving forces are illustrated where the small-sized crowders drive hydrophobic interaction via a classic entropic depletion effect and the bulky crowders strengthen it by preferential interaction with the solute. A crossover from energy-stabilized solvent-separated pair to entropy-stabilized contact pair state is observed in the case of bulky non-polar (Leu2) and polar (Lys2) crowders. The influence of solute-crowder energy in affecting the dehydration energy penalty is found to be crucial for determining the neopentane association. The findings demonstrate that along with the entropic (size) effects, the energetic effects also play a crucial role in determining hydrophobic association. The results can be extended and have implications in understanding the impact of protein crowding with varying chemistry in modulating the protein free energy landscapes.


Assuntos
Proteínas/química , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Solventes/química , Termodinâmica , Água/química
14.
J Chem Phys ; 154(13): 134903, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33832270

RESUMO

Cosolvent effects on the coil-globule transitions in aqueous polymer solutions are not well understood, especially in the case of amphiphilic cosolvents that preferentially adsorb on the polymer and lead to both polymer swelling and collapse. Although a predominant focus in the literature has been placed on the role of polymer-cosolvent attractive interactions, our recent work has shown that excluded-volume interactions (repulsive interactions) can drive both preferential adsorption of the cosolvent and polymer collapse via a surfactant-like mechanism. Here, we further study the role of polymer-(co)solvent attractive interactions in two kinds of polymer solutions, namely, good solvent (water)-good cosolvent (alcohol) (GSGC) and poor solvent-good cosolvent (PSGC) solutions, both of which exhibit preferential adsorption of the cosolvent and a non-monotonic change in the polymer radius of gyration with the addition of the cosolvent. Interestingly, at low concentrations, the polymer-(co)solvent energetic interactions oppose polymer collapse in the GSGC solutions and contrarily support polymer collapse in the PSGC solutions, indicating the importance of the underlying polymer chemistry. Even though the alcohol molecules are preferentially adsorbed on the polymer, the trends of the energetic interactions at low cosolvent concentrations are dominated by the polymer-water energetic interactions in both the cases. Therefore, polymer-(co)solvent energetic interactions can either reinforce or compensate the surfactant-like mechanism, and it is this interplay that drives coil-to-globule transitions in polymer solutions. These results have implications for rationalizing the cononsolvency transitions in real systems such as polyacrylamides in aqueous alcohol solutions where the understanding of microscopic driving forces is still debatable.

15.
Phys Chem Chem Phys ; 22(32): 18091-18101, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32760995

RESUMO

Biomolecules evolve and function in the intracellular crowded environment that is densely packed with macromolecules. Yet, a microscopic understanding of the effects of such an environment on the conformational preferences of biomolecules remains elusive. While prior investigations have attributed crowding effects mainly to the excluded volume (size) effects of the crowders, very little is known about the effects exerted due to their chemical interactions. In this study, crowding effects of tri-alanine peptides on the collapse equilibria of generic hydrophobic polymer are investigated using molecular dynamics simulations. The role of weak, non-specific, attractive polymer-crowder interactions in modulating the polymer collapse equilibria is examined. The results highlight that crowding effects can lead to polymer compaction as well as unfolding depending on the strength of polymer-crowder interaction energy. Strongly interacting crowders weaken hydrophobic collapse (or unfold the polymer) at high volume fractions and induce polymer collapse only under dilute conditions. Weakly interacting crowders induce polymer collapse at all crowder concentrations. Interestingly, the thermodynamic driving forces for polymer collapse are remarkably different in the two cases. Strongly and weakly interacting crowders induce collapse by preferential adsorption and preferential depletion respectively. The findings provide new insights into the possible effects of interplay of intermolecular interactions in a crowded environment. The results have implications in understanding the impact of crowding in altering free energy landscapes of proteins.


Assuntos
Peptídeos/química , Polímeros/química , Interações Hidrofóbicas e Hidrofílicas , Conformação Molecular , Simulação de Dinâmica Molecular
16.
Commun Chem ; 3(1): 165, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36703319

RESUMO

The coil-globule transition of aqueous polymers is of profound significance in understanding the structure and function of responsive soft matter. In particular, the remarkable effect of amphiphilic cosolvents (e.g., alcohols) that leads to both swelling and collapse of stimuli-responsive polymers has been hotly debated in the literature, often with contradictory mechanisms proposed. Using molecular dynamics simulations, we herein demonstrate that alcohols reduce the free energy cost of creating a repulsive polymer-solvent interface via a surfactant-like mechanism which surprisingly drives polymer collapse at low alcohol concentrations. This hitherto neglected role of interfacial solvation thermodynamics is common to all coil-globule transitions, and rationalizes the experimentally observed effects of higher alcohols and polymer molecular weight on the coil-to-globule transition of thermoresponsive polymers. Polymer-(co)solvent attractive interactions reinforce or compensate this mechanism and it is this interplay which drives polymer swelling or collapse.

17.
J Chem Theory Comput ; 14(6): 3298-3310, 2018 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-29715424

RESUMO

Amyloid formation by the intrinsically disordered α-synuclein protein is the hallmark of Parkinson's disease. We present atomistic Molecular Dynamics simulations of the core of α-synuclein using enhanced sampling techniques to describe the conformational and binding free energy landscapes of fragments implicated in fibril stabilization. The theoretical framework is derived to combine the free energy profiles of the fragments into the reaction free energy of a protein binding to a fibril. Our study shows that individual fragments in solution have a propensity toward attaining non-ß conformations, indicating that in a fibril ß-strands are stabilized by interactions with other strands. We show that most dimers of hydrogen-bonded fragments are unstable in solution, while hydrogen bonding stabilizes the collective binding of five fragments to the end of a fibril. Hydrophobic effects make further contributions to the stability of fibrils. This study is the first of its kind where structural and binding preferences of the five major fragments of the hydrophobic core of α-synuclein have been investigated. This approach improves sampling of intrinsically disordered proteins, provides information on the binding mechanism between the core sequences of α-synuclein, and enables the parametrization of coarse grained models.


Assuntos
Amiloide/metabolismo , Simulação de Dinâmica Molecular , alfa-Sinucleína/metabolismo , Amiloide/química , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ressonância Magnética Nuclear Biomolecular , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , alfa-Sinucleína/química
18.
J Phys Chem B ; 122(13): 3587-3595, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29443520

RESUMO

Water-mediated hydrophobic interactions play an important role in self-assembly processes, aqueous polymer solubility, and protein folding, to name a few. Cosolvents affect these interactions; however, the implications for hydrophobic polymer collapse and protein folding equilibria are not well-understood. This study examines cosolvent effects on the hydrophobic collapse equilibrium of a generic 32-mer hydrophobic polymer in urea, trimethylamine- N-oxide (TMAO), and acetone aqueous solutions using molecular dynamics simulations. Our results unveil a remarkable cosolvent-concentration-dependent behavior. Urea, TMAO, and acetone all shift the equilibrium toward collapsed structures below 2 M cosolvent concentration and, in turn, to unfolded structures at higher cosolvent concentrations, irrespective of the differences in cosolvent chemistry and the nature of cosolvent-water interactions. We find that weakly attractive polymer-water van der Waals interactions oppose polymer collapse in pure water, corroborating related observations reviewed by Ben-Amotz ( Annu. Rev. Phys. Chem. 2016, 67, 617-638). The cosolvents studied in the present work adsorb at the polymer/water interface and expel water molecules into the bulk, thereby effectively removing the dehydration energy penalty that opposes polymer collapse in pure water. At low cosolvent concentrations, this leads to cosolvent-induced stabilization of collapsed polymer structures. Only at sufficiently high cosolvent concentrations, polymer-cosolvent interactions favor polymer unfolding.

19.
J Phys Chem B ; 122(21): 5515-5526, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29342355

RESUMO

The computation of Kirkwood-Buff integrals (KBIs) using molecular simulations of closed systems is challenging due to finite system-size effects. One of the problems involves the incorrect asymptotic behavior of the radial distribution function. Corrections to rectify such effects have been proposed in the literature. This study reports a systematic comparison of the proposed corrections (as given by Ganguly et al. J. Chem. Theory Comput. 2013, 9, 1347-1355 and Krüger et al. J. Phys. Chem. Lett. 2013, 4, 4-7) to assess the asymptotic behavior of the RDFs, the KBIs, as well as the estimation of thermodynamic quantities for ideal urea-water and nonideal modified-urea-water mixtures using molecular dynamics simulations. The results show that applying the KBI correction suggested by Krüger et al. on the RDF corrected with the Ganguly et al. correction (denoted as B-KBI) yields improved KBI convergence for the ideal and nonideal aqueous mixtures. Different averaging regions in the running KBIs (correlated or long-range) are assessed, and averaging over the correlated region for large system sizes is found to be robust toward the change in the degree of solvent nonideality and concentration, providing good estimates of thermodynamic quantities. The study provides new insights into improving the KBI convergence, the suitability of different averaging regions in KBIs to estimate thermodynamic properties, as well as the applicability of correction methods to achieve KBI convergence for nonideal aqueous binary mixtures.

20.
J Phys Chem B ; 121(43): 9986-9998, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-28921974

RESUMO

Cosolvents modulate aqueous solubility, hydrophobic interactions, and the stability and function of most proteins in the living cell. Our molecular-level understanding of cosolvent effects is incomplete, not only at the level of complex systems such as proteins, but also at the level of very fundamental interactions that underlie the hydrophobic effect. This Feature Article discusses cosolvent effects on the aqueous solubility of nonpolar solutes, hydrophobic interactions, and hydrophobic self-assembly/collapse of aqueous polymers, recently studied with molecular dynamics simulations. It is shown that direct interactions of cosolvents with nonpolar solutes and aqueous polymers can strengthen hydrophobic interactions and can contribute to stabilizing collapsed globular structures. The molecular-level explanation of these observations requires a better understanding of the entropy associated with fluctuations of attractive solute-solvent interactions and of length-scale dependencies of this quantity.

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