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1.
J Comput Chem ; 36(10): 739-50, 2015 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-25753482

RESUMEN

The Thole induced point dipole model is combined with three different point charge fitting methods, Merz-Kollman (MK), charges from electrostatic potentials using a grid (CHELPG), and restrained electrostatic potential (RESP), and two multipole algorithms, distributed multipole analysis (DMA) and Gaussian multipole model (GMM), which can be used to describe the electrostatic potential (ESP) around molecules in molecular mechanics force fields. This is done to study how the different methods perform when intramolecular polarizability contributions are self-consistently removed from the fitting done in the force field parametrization. It is demonstrated that the polarizable versions of the partial charge models provide a good compromise between accuracy and computational efficiency in describing the ESP of small organic molecules undergoing conformational changes. For the point charge models, the inclusion of polarizability reduced the the average root mean square error of ESP over the test set by 4-10%.

2.
Nanoscale ; 6(14): 8340-9, 2014 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-24934397

RESUMEN

Fullerene and its derivatives with different surface chemistry have great potential in biomedical applications. Accordingly, it is important to delineate the impact of these carbon-based nanoparticles on protein structure, dynamics, and subsequently function. Here, we focused on the effect of hydroxylation - a common strategy for solubilizing and functionalizing fullerene - on protein-nanoparticle interactions using a model protein, ubiquitin. We applied a set of complementary computational modeling methods, including docking and molecular dynamics simulations with both explicit and implicit solvent, to illustrate the impact of hydroxylated fullerenes on the structure and dynamics of ubiquitin. We found that all derivatives bound to the model protein. Specifically, the more hydrophilic nanoparticles with a higher number of hydroxyl groups bound to the surface of the protein via hydrogen bonds, which stabilized the protein without inducing large conformational changes in the protein structure. In contrast, fullerene derivatives with a smaller number of hydroxyl groups buried their hydrophobic surface inside the protein, thereby causing protein denaturation. Overall, our results revealed a distinct role of surface chemistry on nanoparticle-protein binding and binding-induced protein misfolding.


Asunto(s)
Fulerenos/química , Nanopartículas/química , Ubiquitina/química , Sitios de Unión , Calorimetría , Fulerenos/metabolismo , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Hidroxilación , Simulación de Dinámica Molecular , Unión Proteica , Pliegue de Proteína , Ubiquitina/metabolismo
3.
Methods Mol Biol ; 924: 215-41, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23034751

RESUMEN

This chapter provides an overview of the most common methods for including an explicit description of electronic polarization in molecular mechanics force fields: the induced point dipole, shell, and fluctuating charge models. The importance of including polarization effects in biomolecular simulations is discussed, and some of the most important achievements in the development of polarizable biomolecular force fields to date are highlighted.


Asunto(s)
Electrones , Modelos Moleculares , Biopolímeros/química , Termodinámica
4.
J Phys Chem B ; 116(35): 10676-83, 2012 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-22894562

RESUMEN

Experiments have shown that two water-soluble fullerene C(60) derivatives, fullerenol and fullerene trimalonic acid, inhibit duplication of DNA via polymerase chain reaction (PCR). It has further been shown that the target of this inhibition is the DNA polymerase protein routinely used in PCR. We have used a combination of molecular docking and molecular dynamics simulations to study the possible DNA polymerase inhibition mechanisms in atomistic detail. The simulations show structural changes in the tip and two alpha helices of a subdomain, crucial for the polymerase activity, upon fullerene derivative binding. Such tertiary structure changes could prevent the binding of DNA to the protein, causing the inhibition of the PCR process. These findings are in agreement with experimental studies, which have shown that the inhibition is not competitive. The proposed mechanism of inhibition would be common for all DNA polymerase proteins, providing new possibilities in antiviral applications of fullerene derivatives.


Asunto(s)
Fulerenos/química , Polimerasa Taq/antagonistas & inhibidores , Sitios de Unión , ADN/química , ADN/metabolismo , Simulación del Acoplamiento Molecular , Reacción en Cadena de la Polimerasa , Polimerasa Taq/metabolismo
5.
ACS Nano ; 5(8): 6306-14, 2011 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-21761844

RESUMEN

Fullerene derivative C(60)(OH)(20) inhibited microtubule polymerization at low micromolar concentrations. The inhibition was mainly attributed to the formation of hydrogen bonding between the nanoparticle and the tubulin heterodimer, the building block of the microtubule, as evidenced by docking and molecular dynamics simulations. Our circular dichroism spectroscopy measurement indicated changes in the tubulin secondary structures, while our guanosine-5'-triphosphate hydrolysis assay showed hindered release of inorganic phosphate by the nanoparticle. Isothermal titration calorimetry revealed that C(60)(OH)(20) binds to tubulin at a molar ratio of 9:1 and with a binding constant of 1.3 ± 0.16 × 10(6) M(-1), which was substantiated by the binding site and binding energy analysis using docking and molecular dynamics simulations. Our simulations further suggested that occupancy by the nanoparticles at the longitudinal contacts between tubulin dimers within a protofilament or at the lateral contacts of the M-loop and H5 and H12 helices of neighboring tubulins could also influence the polymerization process. This study offered a new molecular-level insight on how nanoparticles may reshape the assembly of cytoskeletal proteins, a topic of essential importance for illuminating cell response to engineered nanoparticles and for the advancement of nanomedicine.


Asunto(s)
Fulerenos/química , Fulerenos/farmacología , Microtúbulos/efectos de los fármacos , Polimerizacion/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fulerenos/metabolismo , Guanosina Trifosfato/metabolismo , Enlace de Hidrógeno , Hidrólisis/efectos de los fármacos , Microtúbulos/química , Microtúbulos/metabolismo , Simulación de Dinámica Molecular , Estructura Secundaria de Proteína/efectos de los fármacos , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
6.
Faraday Discuss ; 144: 411-30; discussion 445-81, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20158041

RESUMEN

Currently, there is no comprehensive model for the dynamics of cellular membranes. The understanding of even the basic dynamic processes, such as lateral diffusion of lipids, is still quite limited. Recent studies of one-component membrane systems have shown that instead of single-particle motions, the lateral diffusion is driven by a more complex, concerted mechanism for lipid diffusion (E. Falck et al., J. Am. Chem. Soc., 2008, 130, 44-45), where a lipid and its neighbors move in unison in terms of loosely defined clusters. In this work, we extend the previous study by considering the concerted lipid diffusion phenomena in many-component raft-like membranes. This nature of diffusion phenomena emerge in all the cases we have considered, including both atom-scale simulations of lateral diffusion within rafts and coarse-grained MARTINI simulations of diffusion in membranes characterized by coexistence of raft and non-raft domains. The data allows us to identify characteristic time scales for the concerted lipid motions, which turn out to range from hundreds of nanoseconds to several microseconds. Further, we characterize typical length scales associated with the correlated lipid diffusion patterns and find them to be about 10 nm, or even larger if weak correlations are taken into account. Finally, the concerted nature of lipid motions is also found in dissipative particle dynamics simulations of lipid membranes, clarifying the role of hydrodynamics (local momentum conservation) in membrane diffusion phenomena.


Asunto(s)
Lípidos de la Membrana/química , Microdominios de Membrana/química , 1,2-Dipalmitoilfosfatidilcolina/química , Simulación por Computador , Difusión , Simulación de Dinámica Molecular
7.
Phys Biol ; 6(4): 046004, 2009 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-19741281

RESUMEN

In this study, the effect of desipramine (DMI) on phospholipid bilayers and parvoviral entry was elucidated. In atomistic molecular dynamics simulations, DMI was found to introduce disorder in cholesterol-rich phospholipid bilayers. This was manifested by a decrease in the deuterium order parameter S(CD) as well as an increase in the membrane area. Disordering of the membrane suggested DMI to destabilize cholesterol-rich membrane domains (rafts) in cellular conditions. To relate the raft disrupting ability of DMI with novel biological relevance, we studied the intracellular effect of DMI using canine parvovirus (CPV), a virus known to interact with endosomal membranes and sphingomyelin, as an intracellular probe. DMI was found to cause retention of the virus in intracellular vesicular structures leading to the inhibition of viral proliferation. This implies that DMI has a deleterious effect on the viral traffic. As recycling endosomes and the internal vesicles of multivesicular bodies are known to contain raft components, the effect of desipramine beyond the plasma membrane step could be caused by raft disruption leading to impaired endosomal function and possibly have direct influence on the penetration of the virus through an endosomal membrane.


Asunto(s)
Membrana Celular/efectos de los fármacos , Colesterol/metabolismo , Simulación por Computador , Desipramina/farmacología , Parvovirus Canino/efectos de los fármacos , Parvovirus Canino/fisiología , Animales , Antidepresivos Tricíclicos/farmacología , Células Cultivadas , Modelos Animales de Enfermedad , Perros , Estructura Molecular
8.
Nanotechnology ; 20(41): 415101, 2009 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-19755724

RESUMEN

The real-time polymerase chain reaction of the plant gene heat shock transcription factor was fully inhibited in the presence of a fullerene derivative C(60)(OH)(20) at a concentration of 4 x 10(-4) mM. This inhibition was attributed to the interaction between the nanoparticle and Taq DNA polymerase in the reaction. Atomistic molecular dynamics simulations showed a clear tendency for hydrogen bonding between C(60)(OH)(20) and both the dNTPs and ssDNA components of the polymerase chain reaction. These studies facilitate our understanding of the fate of nanoparticles in biomolecular systems, a topic of tremendous importance for addressing the biological and environmental implications of nanomaterials.


Asunto(s)
Simulación por Computador , Fulerenos/química , Nanotecnología/métodos , Reacción en Cadena de la Polimerasa/métodos , Modelos Moleculares , Nanopartículas/química , Polimerasa Taq/metabolismo
9.
J Phys Chem B ; 113(7): 1810-2, 2009 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-19199698

RESUMEN

Free volume pockets inside a cell membrane play a prominent role in a variety of dynamic processes such as the permeability of small molecules across membranes and the diffusion of, e.g., lipids, drugs, and electron carriers in the plane of the membrane. Nonetheless, by now the chances for characterizing free volume voids in a nonperturbative manner through experiments have been very limited. Here we use lipid membranes as an example to show how positron annihilation spectroscopy (PALS) together with atomistic simulations can be employed to gauge changes in free volume pockets in biological macromolecular complexes. The measurements show that PALS is a viable technique to probe free volume in biomolecular systems. As examples, we consider the gel-to-fluid transition and the role of increasing cholesterol concentration in a lipid membrane. Further applications proposed in this work for PALS are likely to provide a great deal of insight into the understanding of the role of free volume in the dynamics of biomolecular complexes.


Asunto(s)
Electrones , Membrana Dobles de Lípidos/química , Fluidez de la Membrana , Colesterol/química , Simulación por Computador , Análisis Espectral
10.
Small ; 4(11): 1986-92, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18949789

RESUMEN

Carbon-based nanomaterials possess unique structural, mechanical, and electronic properties that are exploited in numerous applications. The fate of nanomaterials in living systems and in the environment is largely unknown, though there is a reason for concern. Here it is shown how the interaction of fullerene with natural phenolic acid induces cell contraction. This phenomenon has a general applicability to carbon-based nanomaterials interacting with natural amphiphiles. Atomistic simulations reveal that the self-assembly of C(70)-gallic acid (GA) favors aggregation. Confocal fluorescence microscopy shows that C(70)-GA complexes translocate across the membranes of HT-29 cells and enter nuclear membranes. Confocal imaging further reveals the real-time uptake of C(70)-GA and the consequent contraction of the cell membranes. This contraction is attributed to the aggregation of nanoparticles into microsized particles promoted by cell surfaces, a new physical mechanism for deciphering nanotoxicity.


Asunto(s)
Fulerenos/química , Ácido Gálico/química , Modelos Moleculares , Nanopartículas/química , Membrana Nuclear/metabolismo , Fenol/química , Membrana Celular/metabolismo , Simulación por Computador , Células HT29 , Humanos
11.
Traffic ; 9(11): 1839-49, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18647169

RESUMEN

Analysis of sterol distribution and transport in living cells has been hampered by the lack of bright, photostable fluorescent sterol derivatives that closely resemble cholesterol. In this study, we employed atomistic simulations and experiments to characterize a cholesterol compound with fluorescent boron dipyrromethene difluoride linked to sterol carbon-24 (BODIPY-cholesterol). This probe packed in the membrane and behaved similarly to cholesterol both in normal and in cholesterol-storage disease cells and with trace amounts allowed the visualization of sterol movement in living systems. Upon injection into the yolk sac, BODIPY-cholesterol did not disturb zebrafish development and was targeted to sterol-enriched brain regions in live fish. We conclude that this new probe closely mimics the membrane partitioning and trafficking of cholesterol and, because of its excellent fluorescent properties, enables the direct monitoring of sterol movement by time-lapse imaging using trace amounts of the probe. This is, to our knowledge, the first cholesterol probe that fulfills these prerequisites.


Asunto(s)
Compuestos de Boro/química , Colesterol/química , Esteroles/metabolismo , Animales , Transporte Biológico , Células CHO , Cricetinae , Cricetulus , Colorantes Fluorescentes , Inmunohistoquímica , Pez Cebra
12.
J Phys Chem B ; 112(13): 4131-9, 2008 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-18341314

RESUMEN

We have combined experiments with atomic-scale molecular dynamics simulations to consider the influence of ethanol on a variety of lipid membrane properties. We first employed isothermal titration calorimetry together with the solvent-null method to study the partitioning of ethanol molecules into saturated and unsaturated membrane systems. The results show that ethanol partitioning is considerably more favorable in unsaturated bilayers, which are characterized by their more disordered nature compared to their saturated counterparts. Simulation studies at varying ethanol concentrations propose that the partitioning of ethanol depends on its concentration, implying that the partitioning is a nonideal process. To gain further insight into the permeation of alcohols and their influence on lipid dynamics, we also employed molecular dynamics simulations to quantify kinetic events associated with the permeation of alcohols across a membrane, and to characterize the rotational and lateral diffusion of lipids and alcohols in these systems. The simulation results are in agreement with available experimental data and further show that alcohols have a small but non-vanishing effect on the dynamics of lipids in a membrane. The influence of ethanol on the lateral pressure profile of a lipid bilayer is found to be prominent: ethanol reduces the tension at the membrane-water interface and reduces the peaks in the lateral pressure profile close to the membrane-water interface. The changes in the lateral pressure profile are several hundred atmospheres. This supports the hypothesis that anesthetics may act by changing the lateral pressure profile exerted on proteins embedded in membranes.


Asunto(s)
Simulación por Computador , Etanol/química , Membrana Dobles de Lípidos/química , Modelos Químicos , 1,2-Dipalmitoilfosfatidilcolina/química , Calorimetría , Dimiristoilfosfatidilcolina/química , Cinética , Fosfatidilcolinas/química , Presión
13.
Biophys J ; 90(4): 1121-35, 2006 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-16326895

RESUMEN

Extensive microscopic molecular dynamics simulations have been performed to study the effects of short-chain alcohols, methanol and ethanol, on two different fully hydrated lipid bilayer systems (POPC and DPPC) in the fluid phase at 323 K. It is found that ethanol has a stronger effect on the structural properties of the membranes. In particular, the bilayers become more fluid and permeable: ethanol molecules are able to penetrate through the membrane in typical timescales of approximately 200 ns, whereas for methanol that timescale is considerably longer, at least of the order of microseconds. A closer examination exposes a number of effects due to ethanol. Hydrogen-bonding analysis reveals that a large fraction of ethanols is involved in hydrogen bonds with lipids. This in turn is intimately coupled to the ordering of hydrocarbon chains: we find that binding to an ethanol decreases the order of the chains. We have also determined the dependence of lipid-chain ordering on ethanol concentration and found that to be nonmonotonous. Overall, we find good agreement with NMR and micropipette studies.


Asunto(s)
Simulación por Computador , Etanol/química , Membrana Dobles de Lípidos/química , Metanol/química , Modelos Moleculares , 1,2-Dipalmitoilfosfatidilcolina/química , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Fosfatidilcolinas/química , Electricidad Estática , Agua/química
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