[Show abstract][Hide abstract] ABSTRACT: We use molecular simulations to demonstrate the connection between transverse
water-water correlations and wetting phenomena for a range of hydrophobic to
hydrophilic solid surfaces.Near superhydrophobic surfaces, the correlations are
long ranged, system spanning, and are well described by the capillary wave
theory. With increasing surface-water attractions, the correlations are
quenched. At the critical attraction at which long range correlations
disappear, the density profile normal to the surface changes from sigmoidal to
layered, and the fluid begins to wet the surface. This behavior is displayed by
both water and a Lennard-Jones fluid, highlighting the universality of the
[Show abstract][Hide abstract] ABSTRACT: Protein-ligand interactions are central to many biological applications, including molecular recognition, protein formulations, and bioseparations. Complex, multisite ligands can have affinities for different locations on a protein's surface, depending on the chemical and topographical complementarity. We employ an approach based on the spherical harmonic expansion to calculate spatially resolved three-dimensional atomic density profiles of water and ligands in the vicinity of macromolecules. To illustrate the approach, we first study the hydration of model C180 buckyball solutes, with non-spherical patterns of hydrophobicity/philicity on their surface. We extend the approach to calculate density profiles of increasingly complex ligands and their constituent groups around a protein (ubiquitin) in aqueous solution. Analysis of density profiles provides information about the binding face of the protein and the preferred orientations of ligands on the binding surface. Our results highlight that the spherical harmonic expansion based approach is easy to implement and efficient for calculation and visualization of three-dimensional density profiles around spherically non-symmetric and topographically and chemically complex solutes.
The Journal of Physical Chemistry B 09/2014; · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is overwhelming evidence that ions are present near the vapor-liquid interface of aqueous salt solutions. Charged groups can also be driven to interfaces by attaching them to hydrophobic moieties. Despite their importance in many self-assembly phenomena, how ion-ion interactions are affected by interfaces is not understood. We use molecular simulations to show that the effective forces between small ions change character dramatically near the water vapor-liquid interface. Specifically, the water-mediated attraction between oppositely charged ions is enhanced relative to that in bulk water. Further, the repulsion between like-charged ions is weaker than that expected from a continuum dielectric description and can even become attractive as the ions are drawn to the vapor side. We show that thermodynamics of ion association are governed by a delicate balance of ion hydration, interfacial tension, and restriction of capillary fluctuations at the interface, leading to nonintuitive phenomena, such as water-mediated like charge attraction. "Sticky" electrostatic interactions may have important consequences on biomolecular structure, assembly, and aggregation at soft liquid interfaces. We demonstrate this by studying an interfacially active model peptide that changes its structure from α-helical to a hairpin-turn-like one in response to charging of its ends.
Proceedings of the National Academy of Sciences 06/2014; · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We focus on the conformational stability, structure, and dynamics of hydrophobic/charged homo- and heteropolymers at a vapor-liquid interface of water using extensive molecular dynamics simulations. Hydrophobic polymers collapse into globular structures in bulk water, but unfold and sample a broad range of conformations at the vapor-liquid interface of water. We show that adding a pair of charges to a hydrophobic polymer at the interface can dramatically change its conformations, stabilizing hairpin-like structures, with molecular details depending on the location of the charged pair in the sequence. The translational dynamics of homo- and heteropolymers are also different -- whereas the homopolymers skate on the interface with low drag, the tendency of charged groups to remain hydrated pulls the heteropolymers toward the liquid side of the interface, thus pinning them, increasing drag, and slowing the translational dynamics. The conformational dynamics of heteropolymers are also slower than that of the homopolymer, and depend on the location of the charged groups in the sequence. Conformational dynamics are most restricted for the end-charged heteropolymer, and speed up as the charge pair is moved toward the center of the sequence. We rationalize these trends using the fundamental understanding of the effects of the interface on primitive pair-level interactions between two hydrophobic groups or between oppositely charged ions in its vicinity.
[Show abstract][Hide abstract] ABSTRACT: Characterizing the hydrophobicity of a protein surface is relevant to understanding and quantifying its interactions with ligands, other proteins, and extended interfaces. However, the hydrophobicity of a complex, heterogeneous protein surface depends, not only on the chemistry of the underlying amino acids, but also on the precise chemical pattern and topographical context presented by the surface. Characterization of such context-dependent hydrophobicity at nanoscale resolution is a non-trivial task. The free energy, μex, of forming a cavity near a surface has been shown to be a robust measure of context-dependent hydrophobicity, with more favorable μex-values suggesting hydrophobic regions. However, estimating μex for cavities significantly larger than the size of a methane molecule, in a spatially resolved manner near proteins, is a computationally daunting task. Here, we present a new method for estimating μex that is two orders of magnitude more efficient than conventional techniques. Our method envisions cavity creation as the emptying of a volume of interest, v, by applying an external potential that is proportional to the number of water molecules, Nv, in v. We show that the "force" to be integrated to obtain μex is simply the average of N in the presence of the potential, and can be sampled accurately using short simulations (50 - 100 ps), making our method very efficient. By leveraging the efficiency of the method to calculate μex at various locations in the hydration shell of the protein, hydrophobin II, we are able to construct a hydrophobicity map of the protein that accounts for topographical and chemical context. Interestingly, we find that the map is also dependent on the shape and size of v, suggesting an "observer context" in mapping the hydrophobicity of protein surfaces.
The Journal of Physical Chemistry B 01/2014; · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We study how primitive hydrophobic interactions between two or more small non-polar solutes are affected by the presence of surfaces. We show that the desolvation barriers, present in the potential of mean force between the solutes in bulk water, are significantly reduced near an extended hydrophobic surface. Correspondingly, the kinetics of hydrophobic contact formation and breakage are faster near a hydrophobic surface compared to those near a hydrophilic surface or in the bulk. We propose that the reduction in the desolvation barrier is a consequence of the fact that water near extended hydrophobic surfaces is akin to that at a liquid-vapor interface, and is easily displaced. We support this proposal with three independent observations. First, when small hydrophobic solutes are brought near a hydrophobic surface, they induce local dewetting, thereby facilitating the reduction of desolvation barriers. Second, our results and those of Patel et al. (Proc. Natl. Acad. Sci. USA 2011, 108, 17678-17683.) show that while the association of small solutes in bulk water is driven by entropy, that near hydrophobic surfaces is driven by enthalpy, suggesting that the physics of interface deformation is important. Third, moving water away from its vapor-liquid coexistence, by applying hydrostatic pressure, leads to recovery of bulk-like signatures (e.g., the presence of a desolvation barrier, and entropic driving force) in the association of solutes. These observations for simple solutes also translate to end-to-end contact formation in a model peptide with hydrophobic end-groups, for which lowering of the desolvation barrier and speeding up of contact formation are observed near a hydrophobic surface. Our results suggest that extended hydrophobic surfaces, such as air-water or hydrocarbon-water surfaces, may serve as excellent platforms for catalyzing hydrophobically driven assembly.
The Journal of Physical Chemistry B 08/2013; · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TMAO, a potent osmolyte, and TBA, a denaturant, have similar molecular architecture, but somewhat different chemistry. We employ extensive molecular dynamics simulations to quantify their behavior at vapor--water and octane--water interfaces. We show that interfacial structure -- density and orientation -- and their dependence on solution concentration are markedly different for the two molecules. TMAO molecules are moderately surface active, and adopt orientations with their N--O vector approximately parallel to the aqueous interface. That is, not all methyl groups of TMAO at the interface point away from the water phase. In contrast, TBA molecules act as molecular amphiphiles, are highly surface active, and at low concentrations, adopt orientations with their methyl groups pointing away and the C--O vector pointing directly into water. The behavior of TMAO at aqueous interfaces is only weakly dependent on its solution concentration, whereas that of TBA depends strongly on concentration. We show that this concentration dependence arises from their different hydrogen bonding capabilities -- TMAO can only accept hydrogen bonds from water, whereas TBA can accept (donate) hydrogen bonds from (to) water or other TBA molecules. The ability to self-associate, particularly visible in TBA molecules in the interfacial layer, allows them to sample a broad range of orientations at higher concentrations. In light of the role of TMAO and TBA in biomolecular stability, our results provide an excellent reference with which to compare their behavior near biological interfaces. Also, given the ubiquity of aqueous interfaces in biology, chemistry, and technology, our results may be useful in the design of interfacially active small molecules with the aim to control their orientations and interactions.
[Show abstract][Hide abstract] ABSTRACT: The Protein Data Bank contains structures of over 75,000 proteins with atomic resolution, and is growing exponentially. Translating this wealth of static structural information into a molecular understanding of dynamic intracellular processes represents a grand challenge, with progress hinging on our ability to understand biomolecular interactions. Water plays a crucial role in mediating these interactions, in particular through non-specific hydrophobic effects. However, characterizing protein hydrophobicity (and consequently interactions) is challenging, as it depends not only on the chemistry of the underlying surface, but also on surface topography, chemical patterning, size/shape of ligand, etc. We have shown that such context-dependent hydrophobicity depends, not on the mean water density near the protein surface, but on the ease of displacing water from the interfacial region, or alternatively, on the cost of forming cavities near the surface. We have developed novel molecular simulation techniques to efficiently calculate cavity formation free energies. Collectively, our results provide a computational framework for mapping the hydrophobicity of proteins and other complex surfaces, with relevance to developing predictive strategies for biomolecular binding, recognition, and aggregation. Our results also shed light on the driving forces and barriers to hydrophobically driven binding and assembly in interfacial environments. Specifically, we show that water near hydrophobic surfaces is situated at the edge of a dewetting transition that can be triggered by small perturbations. This perspective provides unique insights into diverse phenomena ranging from the formation of amyloid fibrils catalyzed by interfaces, and the function of chaperonins, to the vapor-lock gating mechanism of ion channels.
[Show abstract][Hide abstract] ABSTRACT: Water near extended hydrophobic surfaces is like that at a liquid-vapor interface, where fluctuations in water density are substantially enhanced compared to those in bulk water. Here we use molecular simulations with specialized sampling techniques to show that water density fluctuations are similarly enhanced, even near hydrophobic surfaces of complex biomolecules, situating them at the edge of a dewetting transition. Consequently, water near these surfaces is sensitive to subtle changes in surface conformation, topology, and chemistry, any of which can tip the balance toward or away from the wet state and thus significantly alter biomolecular interactions and function. Our work also resolves the long-standing puzzle of why some biological surfaces dewet and other seemingly similar surfaces do not.
The Journal of Physical Chemistry B 03/2012; 116(8):2498-503. · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interfaces are a most common motif in complex systems. To understand how the presence of interfaces affects hydrophobic phenomena, we use molecular simulations and theory to study hydration of solutes at interfaces. The solutes range in size from subnanometer to a few nanometers. The interfaces are self-assembled monolayers with a range of chemistries, from hydrophilic to hydrophobic. We show that the driving force for assembly in the vicinity of a hydrophobic surface is weaker than that in bulk water and decreases with increasing temperature, in contrast to that in the bulk. We explain these distinct features in terms of an interplay between interfacial fluctuations and excluded volume effects--the physics encoded in Lum-Chandler-Weeks theory [Lum K, Chandler D, Weeks JD (1999) J Phys Chem B 103:4570-4577]. Our results suggest a catalytic role for hydrophobic interfaces in the unfolding of proteins, for example, in the interior of chaperonins and in amyloid formation.
Proceedings of the National Academy of Sciences 10/2011; 108(43):17678-83. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Solid-water interfaces, including those of proteins and membranes, are ubiquitous in the crowded cellular environment. Using molecular simulations and theory, we investigate the manifestations of the hydrophobic effect in these interfacial environments. Specifically, we quantify the hydration thermodynamics of hydrophobic solutes, with sizes ranging from sub-nanometer to a few nanometers, both in bulk water, and near self-assembled monolayers (SAMs) with a range of chemistries, from hydrophilic to hydrophobic. Our results shed light on the thermodynamics of hydrophobically-driven assembly in bulk and at interfaces, as well as that of binding to these interfaces. In particular, the driving force for assembly decreases with increasing temperature near hydrophobic surfaces, in contrast to that in bulk water. Our results also show that hydrophobic forces of assembly in the vicinity of an extended hydrophobic surface are weaker than those in bulk aqueous solution, suggesting a catalytic role for extended hydrophobic interfaces in the unfolding of proteins.
[Show abstract][Hide abstract] ABSTRACT: Traditionally, protein surfaces are characterized as hydrophobic or hydrophilic, based on the nature of the underlying amino-acids, by using hydropathy scales. Recent work has highlighted that the problem of characterizing hydrophobicity at the nano-scale is far more challenging. Water-mediated interactions are often non-additive in nature, and the hydrophobicity of a surface depends not only on the nature of the underlying groups, but also on the nature of the surrounding moieties and the surface topography. Proteins present surfaces that are both heterogeneous and structured to the surrounding water, thereby making it challenging to characterize them. Using molecular simulations, we propose a novel method to quantify the context-dependent hydrophobicity of a protein surface. Specifically, we quantify the ease with which water can be displaced from the hydration shell of the protein surface. In addition to being consistent with macroscopic notions of hydrophobicity, such as the contact angle, for a flat surface, our method is generally applicable, and can be used to characterize the hydrophobicity of nano-structured and heterogeneous surface, such as those of proteins and nanotubes.
[Show abstract][Hide abstract] ABSTRACT: Hydrophobic hydration and hydrophobically-driven assembly play a central role in biology. Recent work has shown that the local water density fluctuations (and not the mean water density), at a solid-water surface, are a robust measure of it’s hydrophobicity. These fluctuations can be quantified by calculating the probability, P(N), of observing N waters in an observation volume (e.g., the hydration shell of a protein) of interest, v. When v is large, calculating P(N) using molecular dynamics simulations is challenging, as the probability of observing very few waters is exponentially small, and the standard procedure for overcoming this problem (umbrella sampling in N leads to undesirable impulsive forces. We have recently developed an indirect umbrella sampling (INDUS) method, that samples a coarse-grained particle number to obtain P(N) in volumes of all shapes and sizes, in a variety of environments, and all thermodynamic conditions. The INDUS method will be of particular interest in characterizing the hydrophobicity of interfaces of proteins, nanotubes and related systems. We have also implemented the ideas underlying the Lum-Chandler-Weeks theory of hydrophobicity into a lattice-based model that is in reasonable quantitative agreement with simulations results, with a 2 to 3 orders of magnitude improvement in computational efficiency.
[Show abstract][Hide abstract] ABSTRACT: A series of simulations and experiments have been carried out to examine the relevant interactions in multimodal chromatographic systems. Molecular dynamics protein-ligand simulations were performed to determine multimodal ligand binding sites on the protein surface. These simulations were found to corroborate experimental data obtained with both NMR and chromatography experiments for a library of homologous protein mutants. Further, these MD simulations were conducted with a combinatorial ligand library to study the role of synergy in the determination of ligand binding sites for these “pseudo-affinity” ligands. All-atom MD simulations were also performed to examine the binding of several proteins to self-assembled monolayers presenting relevant multimodal ligands. Protein adsorption behavior in the presence of various mobile phase modifiers at varying salt concentrations was examined to identify unique selectivity windows and to elucidate the effect of these modifiers on the intermolecular interactions in these systems. Simulations were also carried out with model systems in the presence of these modifiers to evaluate several key hypotheses related to synergistic interactions in these multimodal systems. Finally, novel molecular descriptors based on the molecular simulations were developed and employed to facilitate methods development in these MM systems.
[Show abstract][Hide abstract] ABSTRACT: Water density fluctuations are an important statistical mechanical observable that is related to many-body correlations, as well as hydrophobic hydration and interactions. Local water density fluctuations at a solid-water surface have also been proposed as a measure of it's hydrophobicity. These fluctuations can be quantified by calculating the probability, P(v)(N), of observing N waters in a probe volume of interest v. When v is large, calculating P(v)(N) using molecular dynamics simulations is challenging, as the probability of observing very few waters is exponentially small, and the standard procedure for overcoming this problem (umbrella sampling in N) leads to undesirable impulsive forces. Patel et al. [J. Phys. Chem. B, 114, 1632 (2010)] have recently developed an indirect umbrella sampling (INDUS) method, that samples a coarse-grained particle number to obtain P(v)(N) in cuboidal volumes. Here, we present and demonstrate an extension of that approach to volumes of other basic shapes, like spheres and cylinders, as well as to collections of such volumes. We further describe the implementation of INDUS in the NPT ensemble and calculate P(v)(N) distributions over a broad range of pressures. Our method may be of particular interest in characterizing the hydrophobicity of interfaces of proteins, nanotubes and related systems.
Journal of Statistical Physics 10/2011; 145(2):265-275. · 1.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multimodal chromatography, which employs more than one mode of interaction between ligands and proteins, has been shown to have unique selectivity and high efficacy for protein purification. To test the ability of free solution molecular dynamics (MD) simulations in explicit water to identify binding regions on the protein surface and to shed light on the "pseudo affinity" nature of multimodal interactions, we performed MD simulations of a model protein ubiquitin in aqueous solution of free ligands. Comparisons of MD with NMR spectroscopy of ubiquitin mutants in solutions of free ligands show a good agreement between the two with regard to the preferred binding region on the surface of the protein and several binding sites. MD simulations also identify additional binding sites that were not observed in the NMR experiments. "Bound" ligands were found to be sufficiently flexible and to access a number of favorable conformations, suggesting only a moderate loss of ligand entropy in the "pseudo affinity" binding of these multimodal ligands. Analysis of locations of chemical subunits of the ligand on the protein surface indicated that electrostatic interaction units were located on the periphery of the preferred binding region on the protein. The analysis of the electrostatic potential, the hydrophobicity maps, and the binding of both acetate and benzene probes were used to further study the localization of individual ligand moieties. These results suggest that water-mediated electrostatic interactions help the localization and orientation of the MM ligand to the binding region with additional stability provided by nonspecific hydrophobic interactions.
The Journal of Physical Chemistry B 09/2011; 115(45):13320-7. · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We quantify the Kapitza thermal conductance of solid–liquid interfaces between self-assembled monolayers (SAMs) and liquid water using nonequilibrium molecular dynamics simulations. We focus on understanding how surface chemistry, nanoscale roughness, and the direction of heat flow affect interfacial thermal conductance. In agreement with calculations by Shenogina et al. (Phys. Rev. Lett., 2009, 102, 156101) for SAMs with homogeneous headgroup chemistries, we find that for mixed −CF3/–OH SAMs, thermal conductance increases roughly linearly with the fraction of −OH groups on the surface. Increasing nanoscale roughness increases solid–water contact area, and therefore the apparent thermal conductance. However, the inherent thermal conductance, which accounts for the increased contact area, shows only small and subtle variations. These variations are consistent with expectations based on recent work on the effects of nanoscale roughness on interfacial tension (Mittal and Hummer, Faraday Disc., 2010, 146, 341). Finally, we find that SAM–water interfaces show thermal rectification. Thermal conductance is larger when heat flows from the ordered SAM phase to the disordered liquid water phase, and the magnitude of rectification increases with surface hydrophilicity.
[Show abstract][Hide abstract] ABSTRACT: Macroscopic characterizations of hydrophobicity (e.g., contact angle measurements) do not extend to the surfaces of proteins and nanoparticles. Molecular measures of hydrophobicity of such surfaces need to account for the behavior of hydration water. Theory and state-of-the-art simulations suggest that water density fluctuations provide such a measure; fluctuations are enhanced near hydrophobic surfaces and quenched with increasing surface hydrophilicity. Fluctuations affect conformational equilibria and dynamics of molecules at interfaces. Enhanced fluctuations are reflected in enhanced cavity formation, more favorable binding of hydrophobic solutes, increased compressibility of hydration water, and enhanced water-water correlations at hydrophobic surfaces. These density fluctuation-based measures can be used to develop practical methods to map the hydrophobicity/philicity of heterogeneous surfaces including those of proteins. They highlight that the hydrophobicity of a group is context dependent and is significantly affected by its environment (e.g., chemistry and topography) and especially by confinement. The ability to include information about hydration water in mapping hydrophobicity is expected to significantly impact our understanding of protein-protein interactions as well as improve drug design and discovery methods and bioseparation processes.
Annual Review of Chemical and Biomolecular Engineering 07/2011; 2:147-71. · 8.11 Impact Factor