Shekhar Garde

Rensselaer Polytechnic Institute, Троя, New York, United States

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Publications (119)443.47 Total impact

  • Siddharth Parimal · Shekhar Garde · Steven M Cramer ·
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    ABSTRACT: Fundamental understanding of protein-ligand interactions is important for the development of efficient bioseparations in multimodal chromatography. Here we employ molecular dynamics (MD) simulations to investigate the interactions of three different proteins - ubiquitin, cytochrome C and α-chymotrypsinogen A, sampling a range of charge from +1e to +9e - with two multimodal chromatographic ligands containing similar chemical moieties - aromatic, carboxyl, and amide - in different structural arrangements. We use a spherical harmonic expansion to analyze ligand and individual moiety density profiles around the proteins. We find that the Capto MMC ligand, which contains an additional aliphatic group, displays stronger interactions than Nuvia CPrime ligand with all three proteins. Studying the ligand densities at the moiety level suggests that hydrophobic interactions play a major role in determining the locations of high ligand densities. Finally, the greater structural flexibility of the Capto MMC ligand than that of the Nuvia cPrime ligand, allows for stronger structural complementarity, and enables stronger hydrophobic interactions. These subtle and not-so-subtle differences in binding affinities and modalities for multimodal ligands can result in significantly different binding behavior towards proteins with important implications for bioprocessing.
    Langmuir 06/2015; 31(27). DOI:10.1021/acs.langmuir.5b00236 · 4.46 Impact Factor
  • Shekhar Garde ·

    Journal of biomolecular Structure & Dynamics 05/2015; 33(sup1):97. DOI:10.1080/07391102.2015.1032783 · 2.92 Impact Factor
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    ABSTRACT: Liquid water can become metastable with respect to its vapor in hydrophobic confinement. The resulting dewetting transitions are often impeded by large kinetic barriers. According to macroscopic theory, such barriers arise from the free energy required to nucleate a critical vapor tube that spans the region between two hydrophobic surfaces - tubes with smaller radii collapse, whereas larger ones grow to dry the entire confined region. Using extensive molecular simulations of water between two nanoscopic hydrophobic surfaces, in conjunction with advanced sampling techniques, here we show that for inter-surface separations that thermodynamically favor dewetting, the barrier to dewetting does not correspond to the formation of a (classical) critical vapor tube. Instead, it corresponds to an abrupt transition from an isolated cavity adjacent to one of the confining surfaces to a gap-spanning vapor tube that is already larger than the critical vapor tube anticipated by macroscopic theory. Correspondingly, the barrier to dewetting is also smaller than the classical expectation. We show that the peculiar nature of water density fluctuations adjacent to extended hydrophobic surfaces - namely, the enhanced likelihood of observing low-density fluctuations relative to Gaussian statistics - facilitates this non-classical behavior. By stabilizing isolated cavities relative to vapor tubes, enhanced water density fluctuations thus stabilize novel pathways, which circumvent the classical barriers and offer diminished resistance to dewetting. Our results thus suggest a key role for fluctuations in speeding up the kinetics of numerous phenomena ranging from Cassie-Wenzel transitions on superhydrophobic surfaces, to hydrophobically-driven biomolecular folding and assembly.
    Proceedings of the National Academy of Sciences 02/2015; 112(27). DOI:10.1073/pnas.1503302112 · 9.67 Impact Factor
  • Shekhar Garde ·

    Nature 01/2015; 517(7534):277-9. DOI:10.1038/517277a · 41.46 Impact Factor
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    Eugene Wu · Marc-Olivier Coppens · Shekhar Garde ·
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    ABSTRACT: Arginine-rich proteins (e.g., lysozyme) or poly-L-arginine peptides have been suggested as a solvating and dispersing agent for single wall carbon nanotubes (CNTs) in water. Additionally, protein structure-function in porous and hydrophobic materials is of broad interest. The amino acid residue, arginine (Arg(+)), has been implicated as an important mediator of protein/peptide-CNT interactions. To understand the structural and thermodynamic aspects of this interaction at the molecular level, we employ molecular dynamics simulations of the protein lysozyme in the interior of a CNT as well as of free solutions of Arg(+) in the presence of a CNT. To dissect the Arg(+)-CNT interaction further, we also perform simulations of aqueous solutions of the guanidinium ion (Gdm(+)) and the norvaline (Nva) residue in the presence of a CNT. We show that the interactions of lysozyme with the CNT are mediated by the surface Arg(+) residues. The strong interaction of Arg(+) residue with the CNT is primarily driven by the favorable interactions of the Gdm(+) group with the CNT wall. The Gdm(+) group is less well-hydrated on its flat sides, which binds to the CNT wall. This is consistent with a similar binding of Gdm(+) ions to a hydrophobic polymer. In contrast, the Nva residue, which lacks the Gdm(+) group binds to the CNT weakly. We present details of the free energy of binding, molecular structure, and dynamics of these solutes on the CNT surface. Our results highlight the important role of Arg(+) residues in protein-CNT or protein-carbon-based material interactions. Such interactions could be manipulated precisely through protein engineering, thereby offering control over protein orientation and structure on CNTs, graphene, or other hydrophobic interfaces.
    Langmuir 01/2015; 31(5). DOI:10.1021/la5043553 · 4.46 Impact Factor
  • Eugene Wu · Shekhar Garde ·
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    ABSTRACT: Much attention has been focused on the solvation and density flucutations in water over the past decade. These studies have brought to light interesting physical features of solvation in condensed media, especially the dependence of solvation on the solute lengthscale, which may be general to many fluids. Here, we focus on the lengthscale dependent solvation and density fluctuations in n-octane, a simple organic liquid. Using extensive molecular simulations, we show a crossover in the solvation of solvophobic solutes with increasing size in n-octane, with the specifics of the crossover depending on the shape of the solute. Large lengthscale solvation, which is dominated by interface formation, emerges over sub-nanoscopic lengthscales. The crossover in n-octane occurs at smaller lengthscales than that in water. We connect the lengthscale of crossover to the range of attractive interactions in the fluid. The onset of the crossover is accompanied by the emergence of non-Gaussian tails in density fluctuations in solute shaped observation volumes. Simulations over a range of temperatures highlight a corresponding thermodynamic crossover in solvation. Qualitative similarities between lengthscale-dependent solvation in water, n-octane, and Lennard-Jones fluids highlights the generality of the underlying physics of solvation.
    The Journal of Physical Chemistry B 11/2014; 119(29). DOI:10.1021/jp509912v · 3.30 Impact Factor
  • Lijuan Li · Shekhar Garde ·
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    ABSTRACT: We use molecular dynamics simulations to study the binding, conformations, and dynamics of a flexible 25-mer hydrophobic polymer near well-defined patterned self-assembled monolayers containing a hydrophobic strip (with -CH3 head-groups) having different widths in a hydrophilic (-OH) background. We show that the polymer binds favorably to hydrophobic strips of all widths, including the sub-nanometer ones comprising 3, 2, or even 1 row of -CH3 head-groups, with the binding strength varying from about 107 kJ/mol to 25 kJ/mol for the widest to the narrowest strip. Near wide hydrophobic patches containing 5 or more -CH3 rows, pancake-like conformations are dominant, whereas hairpin-like structures become preferred ones near the narrower strips. In the vicinity of the narrowest 1-row strip, the polymer folds into semi-globular conformations, thus maintaining sufficient contact with the strip while sequestering its hydrophobic groups away from water. We also show that the confinement makes the translational dynamics of the polymer anisotropic as well as conformational dependent. Our results may help understand and manipulate the self-assembly and dynamics of soft matter, such as polymers, peptides and proteins, at inhomogeneous patterned surfaces.
    Langmuir 10/2014; 30(47). DOI:10.1021/la503537b · 4.46 Impact Factor
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    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 underlying physics.
  • Siddharth Parimal · Steven M Cramer · Shekhar Garde ·
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    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; 118(46). DOI:10.1021/jp506849k · 3.30 Impact Factor
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    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; 111(24). DOI:10.1073/pnas.1403294111 · 9.67 Impact Factor
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    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.
    Langmuir 04/2014; 30(16). DOI:10.1021/la500237u · 4.46 Impact Factor

  • 247th National Spring Meeting of the American-Chemical-Society (ACS); 03/2014
  • Amish Jagdish Patel · Shekhar Garde ·
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    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; 118(6). DOI:10.1021/jp4081977 · 3.30 Impact Factor
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    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; 117(35). DOI:10.1021/jp4050513 · 3.30 Impact Factor
  • Andrew Fiore · Vasudevan Venkateshwaran · Shekhar Garde ·
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    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.
    Langmuir 05/2013; 29(25). DOI:10.1021/la401203r · 4.46 Impact Factor
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    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.
    12 AIChE Annual Meeting; 10/2012
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    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. DOI:10.1021/jp2107523 · 3.30 Impact Factor

  • Computational Approaches in Cheminformatics and Bioinformatics, 11/2011: pages 107 - 143; , ISBN: 9781118131411
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    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. DOI:10.1073/pnas.1110703108 · 9.67 Impact Factor
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    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.
    2011 AIChE Annual Meeting; 10/2011

Publication Stats

5k Citations
443.47 Total Impact Points


  • 1999-2015
    • Rensselaer Polytechnic Institute
      • • Department of Chemical and Biological Engineering
      • • Center for Biotechnology and Interdisciplinary Studies
      Троя, New York, United States
  • 1995-2000
    • Los Alamos National Laboratory
      • • Theoretical Division
      • • Theoretical Biology and Biophysics Group
      Los Alamos, CA, United States
  • 1979-1998
    • University of Delaware
      • Center for Molecular and Engineering Thermodynamics
      Newark, DE, United States