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1.  Management of Patients With Pancreatic Cysts 
Supplemental Digital Content is available in the text.
To examine the utility of integrated molecular pathology (IMP) in managing surveillance of pancreatic cysts based on outcomes and analysis of false negatives (FNs) from a previously published cohort (n=492).
In endoscopic ultrasound with fine-needle aspiration (EUS-FNA) of cyst fluid lacking malignant cytology, IMP demonstrated better risk stratification for malignancy at approximately 3 years’ follow-up than International Consensus Guideline (Fukuoka) 2012 management recommendations in such cases.
Patient outcomes and clinical features of Fukuoka and IMP FN cases were reviewed. Practical guidance for appropriate surveillance intervals and surgery decisions using IMP were derived from follow-up data, considering EUS-FNA sampling limitations and high-risk clinical circumstances observed. Surveillance intervals for patients based on IMP predictive value were compared with those of Fukuoka.
Outcomes at follow-up for IMP low-risk diagnoses supported surveillance every 2 to 3 years, independent of cyst size, when EUS-FNA sampling limitations or high-risk clinical circumstances were absent. In 10 of 11 patients with FN IMP diagnoses (2% of cohort), EUS-FNA sampling limitations existed; Fukuoka identified high risk in 9 of 11 cases. In 4 of 6 FN cases by Fukuoka (1% of cohort), IMP identified high risk. Overall, 55% of cases had possible sampling limitations and 37% had high-risk clinical circumstances. Outcomes support more cautious management in such cases when using IMP.
Adjunct use of IMP can provide evidence for relaxed surveillance of patients with benign cysts that meet Fukuoka criteria for closer observation or surgery. Although infrequent, FN results with IMP can be associated with EUS-FNA sampling limitations or high-risk clinical circumstances.
PMCID: PMC4978609  PMID: 27332745
disease management; endoscopic ultrasound-guided fine-needle aspiration; pancreatic cyst; risk
2.  Investigating Hydrophilic Pores in Model Lipid Bilayers using Molecular Simulations: Correlating Bilayer Properties with Pore Formation Thermodynamics 
Cell-penetrating and antimicrobial peptides show remarkable ability to translocate across physiological membranes. Along with factors such as electric potential induced-perturbations of membrane structure and surface tension effects, experiments invoke pore-like membrane configurations during the solute transfer process into vesicles and cells. The initiation and formation of pores are associated with a non-trivial free energy cost, thus necessitating consideration of the factors associated with pore formation and attendant free energetics. Due to experimental and modeling challenges related to the long timescales of the translocation process, we use umbrella-sampling molecular dynamics simulations with a lipid-density based order parameter to investigate membrane pore-formation free energy employing Martini coarse-grained models. We investigate structure and thermodynamic features of the pore in 18 lipids spanning a range of head-groups, charge states, acyl chain lengths and saturation. We probe the dependence of pore-formation barriers on area per lipid, lipid bilayer thickness, membrane bending rigidities in three different lipid classes. The pore formation free energy in pure bilayers and peptide translocating scenarios are significantly coupled with bilayer thickness. Thicker bilayers require more reversible work to create pores. Pore formation free energy is higher in peptide-lipid systems relative to the peptide-free lipid systems due to penalties to maintain solvation of charged hydrophilic solutes within the membrane environment.
PMCID: PMC4934177  PMID: 25614183
3.  Free Energetics of Carbon Nanotube Association in Aqueous Inorganic NaI Salt Solutions: Temperature Effects using All-Atom Molecular Dynamics Simulations 
Journal of computational chemistry  2015;36(16):1196-1212.
In this study we examine the temperature dependence of free energetics of nanotube association by using GPU-enabled all-atom molecular dynamics simulations (FEN ZI) with two (10,10) single-walled carbon nanotubes in 3 m NaI aqueous salt solution. Results suggest that the free energy, enthalpy and entropy changes for the association process are all reduced at the high temperature, in agreement with previous investigations using other hydrophobes. Via the decomposition of free energy into individual components, we found that solvent contribution (including water, anion and cation contributions) is correlated with the spatial distribution of the corresponding species and is influenced distinctly by the temperature. We studied the spatial distribution and the structure of the solvent in different regions: intertube, intra-tube and the bulk solvent. By calculating the fluctuation of coarse-grained tube-solvent surfaces, we found that tube-water interfacial fluctuation exhibits the strongest temperature dependence. By taking ions to be a solvent-like medium in the absence of water, tube-anion interfacial fluctuation also shows similar but weaker dependence on temperature, while tube-cation interfacial fluctuation shows no dependence in general. These characteristics are discussed via the malleability of their corresponding solvation shells relative to the nanotube surface. Hydrogen bonding profiles and tetrahedrality of water arrangement are also computed to compare the structure of solvent in the solvent bulk and intertube region. The hydrophobic confinement induces a relatively lower concentration environment in the intertube region, therefore causing different intertube solvent structures which depend on the tube separation. This study is relevant in the continuing discourse on hydrophobic interactions (as they impact generally a broad class of phenomena in biology, biochemistry, and materials science and soft condensed matter research), and interpretations of hydrophobicity in terms of alternative but parallel signatures such as interfacial fluctuations, dewetting transitions, and enhanced fluctuation probabilities at interfaces.
PMCID: PMC4445429  PMID: 25868455
Hydrophobic Association; Single-Walled Carbon Nanotube; Temperature Dependence; Ion Adsorption; Graphics Processing Unit (GPU)
5.  Association of alkanes with the aqueous liquid-vapor interface: a reference system for interpreting hydrophobicity generally through interfacial fluctuations 
We report free energy calculations and fluctuation profiles of single alkanes (from methane to pentane) along the direction normal to the air-water interface. The induced fluctuations and alkanes’ interfacial stabilities are found to be correlated and similar with the results regarding inorganic monovalent ions (Ou et al., J. Phys. Chem. B, 2013, 117, 11732). This suggests that hydrophobic solvation of solutes and ions is important in determining the adsorption behavior.
PMCID: PMC4237615  PMID: 25372502
6.  Protein Denaturants at Aqueous–Hydrophobic Interfaces: Self-Consistent Correlation between Induced Interfacial Fluctuations and Denaturant Stability at the Interface 
The notion of direct interaction between denaturing cosolvent and protein residues has been proposed in dialogue relevant to molecular mechanisms of protein denaturation. Here we consider the correlation between free energetic stability and induced fluctuations of an aqueous–hydrophobic interface between a model hydrophobically associating protein, HFBII, and two common protein denaturants, guanidinium cation (Gdm+) and urea. We compute potentials of mean force along an order parameter that brings the solute molecule close to the known hydrophobic region of the protein. We assess potentials of mean force for different relative orientations between the protein and denaturant molecule. We find that in both cases of guanidinium cation and urea relative orientations of the denaturant molecule that are parallel to the local protein–water interface exhibit greater stability compared to edge-on or perpendicular orientations. This behavior has been observed for guanidinium/methylguanidinium cations at the liquid–vapor interface of water, and thus the present results further corroborate earlier findings. Further analysis of the induced fluctuations of the aqueous–hydrophobic interface upon approach of the denaturant molecule indicates that the parallel orientation, displaying a greater stability at the interface, also induces larger fluctuations of the interface compared to the perpendicular orientations. The correlation of interfacial stability and induced interface fluctuation is a recurring theme for interface-stable solutes at hydrophobic interfaces. Moreover, observed correlations between interface stability and induced fluctuations recapitulate connections to local hydration structure and patterns around solutes as evidenced by experiment (Cooper et al., J. Phys. Chem. A2014, 118, 5657.) and high-level ab initio/DFT calculations (Baer et al., Faraday Discuss2013, 160, 89).
PMCID: PMC4291035  PMID: 25536388
7.  Reconciling Structural and Thermodynamic Predictions Using All-Atom and Coarse-Grain Force Fields: The Case of Charged Oligo-Arginine Translocation into DMPC Bilayers 
The Journal of Physical Chemistry. B  2014;118(41):11973-11992.
Using the translocation of short, charged cationic oligo-arginine peptides (mono-, di-, and triarginine) from bulk aqueous solution into model DMPC bilayers, we explore the question of the similarity of thermodynamic and structural predictions obtained from molecular dynamics simulations using all-atom and Martini coarse-grain force fields. Specifically, we estimate potentials of mean force associated with translocation using standard all-atom (CHARMM36 lipid) and polarizable and nonpolarizable Martini force fields, as well as a series of modified Martini-based parameter sets. We find that we are able to reproduce qualitative features of potentials of mean force of single amino acid side chain analogues into model bilayers. In particular, modifications of peptide–water and peptide–membrane interactions allow prediction of free energy minima at the bilayer–water interface as obtained with all-atom force fields. In the case of oligo-arginine peptides, the modified parameter sets predict interfacial free energy minima as well as free energy barriers in almost quantitative agreement with all-atom force field based simulations. Interfacial free energy minima predicted by a modified coarse-grained parameter set are −2.51, −4.28, and −5.42 for mono-, di-, and triarginine; corresponding values from all-atom simulations are −0.83, −3.33, and −3.29, respectively, all in units of kcal/mol. We found that a stronger interaction between oligo-arginine and the membrane components and a weaker interaction between oligo-arginine and water are crucial for producing such minima in PMFs using the polarizable CG model. The difference between bulk aqueous and bilayer center states predicted by the modified coarse-grain force field are 11.71, 14.14, and 16.53 kcal/mol, and those by the all-atom model are 6.94, 8.64, and 12.80 kcal/mol; those are of almost the same order of magnitude. Our simulations also demonstrate a remarkable similarity in the structural aspects of the ensemble of configurations generated using the all-atom and coarse-grain force fields. Both resolutions show that oligo-arginine peptides adopt preferential orientations as they translocate into the bilayer. The guiding theme centers on charged groups maintaining coordination with polar and charged bilayer components as well as local water. We also observe similar behaviors related with membrane deformations.
PMCID: PMC4199542  PMID: 25290376
9.  Endoscopic drainage of pancreatic fluid collections using a fully covered expandable metal stent with antimigratory fins 
Endoscopic Ultrasound  2015;4(3):213-218.
Background and Objectives:
Endoscopic drainage is the first consideration in treating pancreatic fluid collections (PFCs). Recent data suggests it may be useful in complicated PFCs as well. Most of the available data assess the use of plastic stents, but scarce data exists on metal stent management of PFCs. The aim of our study to evaluate the efficacy and safety of a metal stent in the management of PFCs.
Patients and Methods:
Data were collected prospectively on 47 patients diagnosed with PFCs from March 2007 to August 2011 at 3 tertiary care centers. These patients underwent endoscopic transmural placement of a fully covered self-expanding metal stent (FCSEMS) with antimigratory fins of 10 mm diameter.
The stent was successfully placed in all patients, and left in place an average of 13 weeks (range 0.4-36 weeks). Etiology of the PFC was biliary pancreatitis (23), pancreas divisum (2), trauma (4), hyperlipidemia (3), alcoholic (8), smoking (2), idiopathic (4), and medication-induced (1). PFCs resolved in 36 patients, for an overall success rate of 77%. Complications included fever (3), stent migration (2) and abdominal pain (1).
The use of FCSEMS is successful in the majority of patients with low complication rates. A large sample-sized RCT is needed to confirm if the resolution of PFCs is long-standing.
PMCID: PMC4568633  PMID: 26374579
Endoscopy; fully covered self-expanding metal stent with antimigratory fins; pancreatic fluid collections; transmural
10.  Ion-Specific Induced Fluctuations and Free Energetics of Aqueous Protein Hydrophobic Interfaces: Toward Connecting to Specific-Ion Behaviors at Aqueous Liquid–Vapor Interfaces 
The Journal of Physical Chemistry. B  2014;118(17):4490-4504.
We explore anion-induced interface fluctuations near protein–water interfaces using coarse-grained representations of interfaces as proposed by Willard and Chandler (J. Phys. Chem. B2010, 114, 1954−195820055377). We use umbrella sampling molecular dynamics to compute potentials of mean force along a reaction coordinate bridging the state where the anion is fully solvated and one where it is biased via harmonic restraints to remain at the protein–water interface. Specifically, we focus on fluctuations of an interface between water and a hydrophobic region of hydrophobin-II (HFBII), a 71 amino acid residue protein expressed by filamentous fungi and known for its ability to form hydrophobically mediated self-assemblies at interfaces such as a water/air interface. We consider the anions chloride and iodide that have been shown previously by simulations as displaying specific-ion behaviors at aqueous liquid–vapor interfaces. We find that as in the case of a pure liquid–vapor interface, at the hydrophobic protein–water interface, the larger, less charge-dense iodide anion displays a marginal interfacial stability compared with that of the smaller, more charge-dense chloride anion. Furthermore, consistent with the results at aqueous liquid–vapor interfaces, we find that iodide induces larger fluctuations of the protein–water interface than chloride.
PMCID: PMC4010293  PMID: 24701961
11.  Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity 
The Journal of Physical Chemistry. B  2014;118(10):2670-2682.
Structural mechanisms and underlying thermodynamic determinants of efficient internalization of charged cationic peptides (cell-penetrating peptides, CPPs) such as TAT, polyarginine, and their variants, into cells, cellular constructs, and model membrane/lipid bilayers (large and giant unilamellar or multilamelar vesicles) continue to garner significant attention. Two widely held views on the translocation mechanism center on endocytotic and nonendocytotic (diffusive) processes. Espousing the view of a purely diffusive internalization process (supported by recent experimental evidence, [Säälik, P.; et al. J. Controlled Release2011, 153, 117–125]), we consider the underlying free energetics of the translocation of a nonaarginine peptide (Arg9) into a model DPPC bilayer. In the case of the Arg9 cationic peptide, recent experiments indicate a higher internalization efficiency of the cyclic structure (cyclic Arg9) relative to the linear conformer. Furthermore, recent all-atom resolution molecular dynamics simulations of cyclic Arg9 [Huang, K.; et al. Biophys. J., 2013, 104, 412–420] suggested a critical stabilizing role of water- and lipid-constituted pores that form within the bilayer as the charged Arg9 translocates deep into the bilayer center. Herein, we use umbrella sampling molecular dynamics simulations with coarse-grained Martini lipids, polarizable coarse-grained water, and peptide to explore the dependence of translocation free energetics on peptide structure and conformation via calculation of potentials of mean force along preselected reaction paths allowing and preventing membrane deformations that lead to pore formation. Within the context of the coarse-grained force fields we employ, we observe significant barriers for Arg9 translocation from bulk aqueous solution to bilayer center. Moreover, we do not find free-energy minima in the headgroup–water interfacial region, as observed in simulations using all-atom force fields. The pore-forming paths systematically predict lower free-energy barriers (ca. 90 kJ/mol lower) than the non pore-forming paths, again consistent with all-atom force field simulations. The current force field suggests no preference for the more compact or covalently cyclic structures upon entering the bilayer. Decomposition of the PMF into the system’s components indicates that the dominant stabilizing contribution along the pore-forming path originates from the membrane as both layers of it deformed due to the formation of pore. Furthermore, our analysis revealed that although there is significant entropic stabilization arising from the enhanced configurational entropy exposing more states as the peptide moves through the bilayer, the enthalpic loss (as predicted by the interactions of this coarse-grained model) far outweighs any former stabilization, thus leading to significant barrier to translocation. Finally, we observe reduction in the translocation free-energy barrier for a second Arg9 entering the bilayer in the presence of an initial peptide restrained at the center, again, in qualitative agreement with all-atom force fields.
PMCID: PMC3983342  PMID: 24506488
13.  Operating theatre time, where does it all go? A prospective observational study 
The BMJ  2014;349:g7182.
Objective To assess the accuracy of surgeons and anaesthetists in predicting the time it will take them to complete an operation or procedure and therefore explain some of the difficulties encountered in operating theatre scheduling.
Design Single centre, prospective observational study.
Setting Plastic, orthopaedic, and general surgical operating theatres at a level 1 trauma centre serving a population of about 370 000.
Participants 92 operating theatre staff including surgical consultants, surgical registrars, anaesthetic consultants, and anaesthetic registrars.
Intervention Participants were asked how long they thought their procedure would take. These data were compared with actual time data recorded at the end of the case.
Primary outcome measure Absolute difference between predicted and actual time.
Results General surgeons underestimated the time required for the procedure by 31 minutes (95% confidence interval 7.6 to 54.4), meaning that procedures took, on average, 28.7% longer than predicted. Plastic surgeons underestimated by 5 minutes (−12.4 to 22.4), with procedures taking an average of 4.5% longer than predicted. Orthopaedic surgeons overestimated by 1 minute (−16.4 to 14.0), with procedures taking an average of 1.1% less time than predicted. Anaesthetists underestimated by 35 minutes (21.7 to 48.7), meaning that, on average, procedures took 167.5% longer than they predicted. The four specialty mean time overestimations or underestimations are significantly different from each other (P=0.01). The observed time differences between anaesthetists and both orthopaedic and plastic surgeons are significantly different (P<0.05), but the time difference between anaesthetists and general surgeons is not significantly different.
Conclusion The inability of clinicians to predict the necessary time for a procedure is a significant cause of delay in the operating theatre. This study suggests that anaesthetists are the most inaccurate and highlights the potential differences between specialties in what is considered part of the “anaesthesia time.”
PMCID: PMC4266034  PMID: 25510241
14.  Coronary Artery Aneurysms in a 15-Year-Old Boy 
Texas Heart Institute Journal  2014;41(6):675-676.
PMCID: PMC4251349  PMID: 25593542
15.  Free Energetics of Arginine Permeation into Model DMPC Lipid Bilayers: Coupling of Effective Counterion Concentration and Lateral Bilayer Dimensions 
The journal of physical chemistry. B  2013;117(39):11641-11653.
Mechanisms and underlying thermodynamic determinants of translocation of charged cationic peptides such as cell-penetrating peptides across the cellular membrane continue to receive much attention. Two widely-held views include endocytotic and non-endocytotic (diffusive) processes of permeant transfer across the bilayer. Considering a purely diffusive process, we consider the free energetics of translocation of a mono-arginine peptide mimic across a model DMPC bilayer. We compute potentials of mean force for the transfer of a charged mono-arginine peptide unit from water to the center of a 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) model lipid bilayer. We use fully atomistic molecular dynamics simulations coupled with the adaptive biasing force (ABF) method for free energy estimation. The estimated potential of mean force difference from bulk to bilayer center is 6.94 ± 0.28 kcal/mol. The order of magnitude of this prediction is consistent with past experimental estimates of arginine partitioning into physiological bilayers in the context of translocon-based experiments, though the correlation between the bench and computer experiments is not unambiguous. Moreover, the present value is roughly one-half of previous estimates based on all-atom molecular dynamics free energy calculations. We trace the differences between the present and earlier calculations to system sizes used in the simulations, and the dependence of the contributions to the free energy from various system components (water, lipids, ions, peptide) on overall system size. By varying the bilayer lateral dimensions in simulations using only sufficient numbers of counterions to maintain overall system charge neutrality, we find the possibility of an inherent convergent transfer free energy value.
PMCID: PMC4219256  PMID: 23888915
molecular dynamics; biological membranes; thermodynamic stability; charged amino acids
16.  Charge Equilibration Force Fields for Molecular Dynamics Simulations of Lipids, Bilayers, and Integral Membrane Protein Systems 
Biochimica et biophysica acta  2011;1818(2):318-329.
With the continuing advances in computational hardware and novel force fields constructed using quantum mechanics, the outlook for non-additive force fields is promising. Our work in the past several years has demonstrated the utility of polarizable force fields, those based on the charge equilibration formalism, for a broad range of physical and biophysical systems. We have constructed and applied polarizable force fields for lipids and lipid bilayers. In this review of our recent work, we discuss the formalism we have adopted for implementing the charge equilibration (CHEQ) method for lipid molecules. We discuss the methodology, related issues, and briefly discuss results from recent applications of such force fields. Application areas include DPPC-water monolayers, potassium ion permeation free energetics in the gramicidin A bacterial channel, and free energetics of permeation of charged amino acid analogues across the water-bilayer interface.
PMCID: PMC4216680  PMID: 21967961
17.  Liquid-Vapor Interfacial Properties of Aqueous Solutions of Guanidinium and Methyl Guanidinium Chloride: Influence of Molecular Orientation on Interface Fluctuations 
The journal of physical chemistry. B  2013;117(39):11719-11731.
The guanidinium cation (C(NH2)3+) is a highly stable cation in aqueous solution due to its efficient solvation by water molecules and resonance stabilization of the charge. Its salts increase the solubility of nonpolar molecules (”salting-in”) and decrease the ordering of water. It is one of the strongest denaturants used in biophysical studies of protein folding. We investigate the behavior of guanidinium and its derivative, methyl guanidinium (an amino acid analogue) at the air-water surface, using atomistic molecular dynamics (MD) simulations and calculation of potentials of mean force. Methyl guanidinium cation is less excluded from the air-water surface than guanidinium cation, but both cations show orientational dependence of surface affinity. Parallel orientations of the guanidinium ring (relative to the Gibbs dividing surface) show pronounced free energy minima in the interfacial region, while ring orientations perpendicular to the GDS exhibit no discernible surface stability. Calculations of surface fluctuations demonstrate that near the air-water surface, the parallel-oriented cations generate significantly greater interfacial fluctuations compared to other orientations, which induces more long-ranged perturbations and solvent density redistribution. Our results suggest a strong correlation with induced interfacial fluctuations and ion surface stability. These results have implications for interpreting molecular-level, mechanistic action of this osmolyte’s interaction with hydrophobic interfaces as they impact protein denaturation (solubilization).
PMCID: PMC4216681  PMID: 23937431
molecular dynamics; guanidinium; interface; fluctuations
18.  Dynamics and Energetics of Hydrophobically Confined Water 
PMCID: PMC4214077  PMID: 23004766
19.  Electrostatic Properties of Aqueous Salt Solution Interfaces: A Comparison of Polarizable and Non-Polarizable Ion Models 
The journal of physical chemistry. B  2008;112(37):11679-11693.
The effects of ion force field polarizability on the interfacial electrostatic properties of ~1 M aqueous solutions of NaCl, CsCl and NaI are investigated using molecular dynamics simulations employing both non-polarizable and Drude-polarizable ion sets. Differences in computed depth-dependent orientational distributions, “permanent” and induced dipole and quadrupole moment profiles, and interfacial potentials are obtained for both ion sets to further elucidate how ion polarizability affects interfacial electrostatic properties among the various salts relative to pure water. We observe that the orientations and induced dipoles of water molecules are more strongly perturbed in the presence of polarizable ions via a stronger ionic double layer effect arising from greater charge separation. Both anions and cations exhibit enhanced induced dipole moments and strong z alignment in the vicinity of the Gibbs dividing surface (GDS) with the magnitude of the anion induced dipoles being nearly an order of magnitude larger than those of the cations and directed into the vapor phase. Depth-dependent profiles for the trace and zz components of the water molecular quadrupole moment tensors reveal 40% larger quadrupole moments in the bulk phase relative to the vapor mimicking a similar observed 40% increase in the average water dipole moment. Across the GDS, the water molecular quadrupole moments increase non-monotonically (in contrast to the water dipoles) and exhibit a locally reduced contribution just below the surface due to both orientational and polarization effects. Computed interfacial potentials for the non-polarizable salts yield values 20 to 60 mV more positive than pure water and increase by an additional 30 to 100 mV when ion polarizability is included. A rigorous decomposition of the total interfacial potential into ion monopole, water and ion dipole, and water quadrupole components reveals that a very strong, positive ion monopole contribution is offset by negative contributions from all other potential sources. Water quadrupole components modulated by the water density contribute significantly to the observed interfacial potential increments and almost entirely explain observed differences in the interfacial potentials for the two chloride salts. By lumping all remaining non-quadrupole interfacial potential contributions into a single “effective” dipole potential, we observe that the ratio of quadrupole to “effective” dipole contributions range from 2:1 in CsCl to 1:1.5 in NaI suggesting that both contributions are comparably important in determining the interfacial potential increments. We also find that oscillations in the quadrupole potential in the double layer region are opposite in sign and partially cancel those of the “effective” dipole potential.
PMCID: PMC4214153  PMID: 18712908
20.  Binding Structures of tri-N-acetyl-β-glucosamine in Hen Egg White Lysozyme using Molecular Dynamics with a Polarizable Force Field 
Lysozyme is a well-studied enzyme that hydrolyzes the β-(1,4)-glycosidic linkage of N-acetyl-β-glucosamine (NAG)n oligomers. The active site of hen egg-white lysozyme (HEWL) is believed to consist of six subsites, A-F that can accommodate six sugar residues. We present studies exploring the use of polarizable force fields in conjunction with all-atom molecular dynamics simulations to analyze binding structures of complexes of lysozyme and NAG trisaccharide, (NAG)3. Molecular dynamics trajectories are applied to analyze structures and conformation of the complex as well as protein-ligand interactions, including the hydrogen-bonding network in the binding pocket. Two binding modes (ABC and BCD) of (NAG)3 are investigated independently based on a fixed-charge model and a polarizable model. We also apply MM-GBSA methods based on molecular dynamics using both non-polarizable and polarizable force fields in order to compute binding free energies. We also study the correlation between RMSD and binding free energies of the wildtype and W62Y mutant; we find that for this prototypical system, approaches using the MD trajectories coupled with implicit solvent models are equivalent for polarizable and fixed-charge models.
PMCID: PMC4214157  PMID: 23109228
21.  Interfacial Structure, Thermodynamics, and Electrostatics of Aqueous Methanol Solutions via Molecular Dynamics Simulations Using Charge Equilibration Models 
The journal of physical chemistry. B  2009;113(27):9241-9254.
We present results from molecular dynamics simulations of methanol-water solutions using charge equilibration force fields to explicitly account for non-additive electronic interaction contributions to the potential energy. We study solutions across the concentration range from 0.1 to 0.9 methanol mole fraction. At dilute concentrations, methanol density is enhanced at the liquid-vapor interface, consistent with previous molecular dynamics and experimental studies. Interfacial thickness exhibits a monotonic increase with increasing methanol mole fraction, while surface tensions display monotonic decrease with methanol concentration, in qualitative agreement with experimental data and previous molecular dynamics predictions using polarizable force fields. In terms of interfacial structure, in keeping with predictions of traditional force fields, there is a unique preferential orientation of methanol molecules at the interface. Moreover, there is a free energetic preference for methanol molecules at the interface as evidenced by potential of mean force calculations. The pmf calculations suggest an interfacial state with 0.8 kcal/mole stability relative to the bulk, again, in qualitative agreement with previous simulation and experimental studies. Interfacial potentials based on double integration of total charge density range from −610 mV to −330 mV over the dilute to concentrated regimes, respectively. The preponderance of methanol at the interface at all mole fractions gives rise to a dominant methanol contribution to the total interfacial potential. Interestingly, there is a transition of the water surface potential contribution from negative to positive upon the transition from methanol mole fraction of 0.1 to 0.2. The dipole and quadrupole contributions to the water component of the total interfacial potential are effectively of equal magnitude and opposite sign, thus canceling one another. We compute the in-plane component of the dielectric permittivity along the interface normal. We observe a non-monotonic behavior of the methanol in-plane dielectric permittivity that tracks the methanol density profiles at low methanol mole fractions. At higher methanol mole fractions, the total in-plane permittivity is dominated by methanol, and displays a monotonic decrease from bulk to vapor. We finally probe the nature of hydration of water in the bulk versus interfacial regions for methanol mole fractions of 0.1 and 0.2. In the bulk, methanol perturbs water structure so as to give rise to water hydrogen bond excesses. Moreover, we observe negative hydrogen bond excess in the vicinity of the alkyl group, as reported by Zhong et al for bulk ethanol-water solutions using charge equilibration force fields, and positive excess in regions hydrogen bonding to nearest-neighbor methanol molecules. Within the interfacial region, water and methanol density reduction lead to concomitant water hydrogen bond deficiencies (negative hydrogen-bond excess).
PMCID: PMC4214159  PMID: 19569724
22.  Thermodynamic and Structural Properties of Methanol-Water Solutions Using Non-Additive Interaction Models 
Journal of computational chemistry  2008;29(7):1142-1152.
We study bulk structural and thermodynamic properties of methanol-water solutions via molecular dynamics simulations using novel interaction potentials based on the charge equilibration (fluctuating charge) formalism to explicitly account for molecular polarization at the atomic level. The study uses the TIP4P-FQ potential for water-water interactions, and the CHARMM-based (Chemistry at HARvard Molecular Mechanics) fluctuating charge potential for methanol-methanol and methanol-water interactions. In terms of bulk solution properties, we discuss liquid densities, enthalpies of mixing, dielectric constants, self-diffusion constants, as well as structural properties related to local hydrogen bonding structure as manifested in radial distribution functions and cluster analysis. We further explore the electronic response of water and methanol in the differing local environments established by the interaction of each species predominantly with molecules of the other species. The current force field for the alcohol-water interaction performs reasonably well for most properties, with the greatest deviation from experiment observed for the excess mixing enthalpies, which are predicted to be too favorable. This is qualitatively consistent with the overestimation of the methanol-water gas-phase interaction energy for the lowest-energy conformer (methanol as proton donor). Hydration free energies for methanol in TIP4P-FQ water are predicted to be −5.6±0.2 kcal/mole, in respectable agreement with the experimental value of −5.1 kcal/mole. With respect to solution micro-structure, the present cluster analysis suggests that the micro-scale environment for concentrations where select thermodynamic quantities reach extremal values is described by a bi-percolating network structure.
PMCID: PMC4212651  PMID: 18074339
methanol; water; aqueous solutions; polarizable force field; fluctuating charge; non-additive interactions
23.  Spherical Monovalent Ions at Aqueous Liquid-Vapor Interfaces: Interfacial Stability and Induced Interface Fluctuations 
The journal of physical chemistry. B  2013;117(39):11732-11742.
Ion-specific interfacial behaviors of monovalent halides impact processes such as protein denaturation, interfacial stability, surface tension modulation, and as such, their molecular and thermodynamic underpinnings garner much attention. We use molecular dynamics simulations of monovalent anions in water to explore effects on distant interfaces. We observe long-ranged ion-induced perturbations of the aqueous environment as suggested by experiment and theory. Surface stable ions, characterized as such by minima in potentials of mean force computed using umbrella sampling MD simulations, induce larger interfacial fluctuations compared to non-surface active species, conferring more entropy approaching the interface. Smaller anions and cations show no interfacial potential of mean force minima. The difference is traced to hydration shell properties of the anions, and the coupling of these shells with distant solvent. The effects correlate with the positions of the anions in the Hofmeister series (acknowledging variations in force field ability to recapitulate essential underlying physics), suggesting how differences in induced, non-local perturbations of interfaces may be related to different specific-ion effects in dilute biophysical and nanomaterial systems.
PMCID: PMC4210775  PMID: 24032752
ions; liquid-vapor interface; surface-stability; Hofmeister; fluctuations
24.  Temperature Dependence and Energetics of Single Ions at the Aqueous Liquid-Vapor Interface 
The journal of physical chemistry. B  2013;117(21):6512-6523.
We investigate temperature-dependence of free energetics with two single halide anions, I− and Cl−, crossing the aqueous liquid-vapor interface through molecular dynamics simulations. The result shows that I− has a modest surface stability of 0.5 kcal/mol at 300 K and the stability decreases as the temperature increases, indicating the surface adsorption process for the anion is entropically disfavored. In contrast, Cl− shows no such surface state at all temperatures. Decomposition of free energetics reveals that water-water interactions provide a favorable enthalpic contribution, while the desolvation of ion induces an increase in free energy. Calculations of surface fluctuations demonstrate that I− generates significantly greater interfacial fluctuations compared to Cl−. The fluctuation is attributed to the malleability of the solvation shells, which allows for more long-ranged perturbations and solvent density redistribution induced by I− as the anion approaches the liquid-vapor interface. The increase in temperature of the solvent enhances the inherent thermally-excited fluctuations and consequently reduces the relative contribution from anion to surface fluctuations, which is consistent with the decrease in surface-stability of I−. Our results indicate a strong correlation with induced interfacial fluctuations and anion surface stability; moreover, resulting temperature dependent behavior of induced fluctuations suggests the possibility of a critical level of induced fluctuations associated with surface stability.
PMCID: PMC4210776  PMID: 23537166
ions; liquid-vapor interface; surface-stability; Hofmeister; fluctuations
25.  Role of Spatial Ionic Distribution on the Energetics of Hydrophobic Assembly and Properties of the Water/Hydrophobe Interface† 
We present results from all-atom molecular dynamics simulations of large-scale hydrophobic plates solvated in NaCl and NaI salt solutions. As observed in studies of ions at the air-water interface, the density of iodide near the water-plate interface is significantly enhanced relative to chloride and in the bulk. This allows for the partial hydration of iodide while chloride remains more fully hydrated. In 1M solutions, iodide directly pushes the hydrophobes together (contributing −2.51 kcal/mol) to the PMF. Chloride, however, strengthens the water-induced contribution to the PMF by ~ −2.84 kcal/mol. These observations are enhanced in 3M solutions, consistent with the increased ion density in the vicinity of the hydrophobes. The different salt solutions influence changes in the critical hydrophobe separation distance and characteristic wetting/dewetting transitions. These differences are largely influenced by the ion-specific expulsion of iodide from bulk water. Results of this study are of general interest to the study of ions at interfaces and may lend insight to the mechanisms underlying the Hofmeister series.
PMCID: PMC4211274  PMID: 22231014

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