Sanjoy Bandyopadhyay

Towards an Understanding of Complex Biological Membranes from Atomistic Molecular Dynamics Simulations

Computer simulation has emerged as a powerful tool for studying the structural and functional properties of complex biological membranes. In the last few years, the use of recently developed simulation methodologies and current generation force fields has permitted novel applications of molecular dynamics simulations, which have enhanced our understanding of the different physical processes governing biomembrane structure and dynamics. This review focuses on frontier areas of research with important biomedical applications. We have paid special attention to polyunsaturated lipids, membrane proteins and ion channels, surfactant additives in membranes, and lipid–DNA gene transfer complexes.

Molecular Dynamics Study of a Surfactant Monolayer Adsorbed at the Air/Water Interface.

A constant volume and temperature (NVT) molecular dynamics (MD) simulation has been carried out to investigate the properties of a monolayer of monododecyl hexaethylene glycol (C12E6) adsorbed at the air/water interface at a surface coverage corresponding to that at its critical micelle concentration (55 Å(2) per molecule). The simulated results have been found to agree reasonably well with available experimental data and with other simulation studies. The study shows that the long polar headgroups of the surfactants are more tilted toward the aqueous layer due to strong interaction between them and water. It has been shown that the surfactant monolayer strongly influences the translational and rotational mobility of interfacial water molecules. A drastic change in the dipolar reorientational motion of water molecules in the aqueous layer is observed with a small variation of distance from the surfactant headgroups.

Importance of Protein Conformational Motions and Electrostatic Anchoring Sites on the Dynamics and Hydrogen Bond Properties of Hydration Water

The microscopic dynamic properties of water molecules present in the vicinity of a protein are expected to be sensitive to its local conformational motions and the presence of polar and charged groups at the surface capable of anchoring water molecules through hydrogen bonds. In this work, we attempt to understand such sensitivity by performing detailed molecular dynamics simulations of the globular protein barstar solvated in aqueous medium. Our calculations demonstrate that enhanced confinement at the protein surface on freezing its local motions leads to increasingly restricted water mobility with long residence times around the secondary structures. It is found that the inability of the surface water molecules to bind with the protein residues by hydrogen bonds in the absence of protein-water (PW) electrostatic interactions is compensated by enhanced water-water hydrogen bonds around the protein with uniform bulklike behaviors. Importantly, it is further noticed that in contrast to the PW hydrogen bond relaxation time scale, the kinetics of the breaking and formation of such bonds are not affected on freezing the proteins conformational motions.

Differential flexibility of the secondary structures of lysozyme and the structure and ordering of surrounding water molecules

We have performed an atomistic molecular dynamics simulation of an aqueous solution of hen egg-white lysozyme at room temperature with explicit water molecules. Several analyses have been carried out to explore the differential flexibility of the secondary structural segments of the protein and the structure and ordering of water around them. It is found that the overall flexibility of the protein molecule is primarily controlled by few large-amplitude bistable motions exhibited by two coils; one connecting two α-helical segments in domain-1 and the other connecting a 3(10) helix and a β-sheet in domain-2 of the protein. The heterogeneous structuring of water around the segments of the protein has been found to depend on the degree of exposure of the segments to water. The ordering of water molecules around the protein segments and their tagged potential energies have been found to be anticorrelated with each other. Some of these findings can be verified by suitable experimental studies.

Molecular dynamics studies of aqueous surfactants systems

Abstract Recent progress in the characterization of aqueous surfactant systems using molecular dynamics simulations is reviewed, and insights into the structure and dynamical behavior of three systems are presented. In the first example we study the formation of an ethanol monolayer at the air/water interface. The second example is an investigation of the structure and the dynamics of nanoscale aqueous droplets, similar to those encountered in nucleation of binary systems from the gaseous phase. Finally, we report recent results on attempts to follow the self assembly of micellar aggregates from surfactant monomers in solutions.

Dynamic properties of water around a protein–DNA complex from molecular dynamics simulations

Formation of protein-DNA complex is an important step in regulation of genes in living organisms. One important issue in this problem is the role played by water in mediating the protein-DNA interactions. In this work, we have carried out atomistic molecular dynamics simulations to explore the heterogeneous dynamics of water molecules present in different regions around a complex formed between the DNA binding domain of human TRF1 protein and a telomeric DNA. It is demonstrated that such heterogeneous water motions around the complex are correlated with the relaxation time scales of hydrogen bonds formed by those water molecules with the protein and DNA. The calculations reveal the existence of a fraction of extraordinarily restricted water molecules forming a highly rigid thin layer in between the binding motifs of the protein and DNA. It is further proved that higher rigidity of water layers around the complex originates from more frequent reformations of broken water-water hydrogen bonds. Importantly, it is found that the formation of the complex affects the transverse and longitudinal degrees of freedom of surrounding water molecules in a nonuniform manner.

Hydration Behavior at the Ice-Binding Surface of the Tenebrio molitor Antifreeze Protein

Molecular dynamics (MD) simulations have been carried out at two different temperatures (300 and 220 K) to study the conformational rigidity of the hyperactive Tenebrio molitor antifreeze protein (TmAFP) in aqueous medium and the structural arrangements of water molecules hydrating its surface. It is found that irrespective of the temperature the ice-binding surface (IBS) of the protein is relatively more rigid than its nonice-binding surface (NIBS). The presence of a set of regularly arranged internally bound water molecules is found to play an important role in maintaining the flat rigid nature of the IBS. Importantly, the calculations reveal that the strategically located hydroxyl oxygens of the threonine (Thr) residues in the IBS influence the arrangements of five sets of ordered waters around it on two parallel planes that closely resemble the basal plane of ice. As a result, these waters can register well with the ice basal plane, thereby allowing the IBS to preferentially bind at the ice interface and inhibit its growth. This provides a possible molecular reason behind the ice-binding activity of TmAFP at the basal plane of ice.

Hydration Properties of α-, β-, and γ-Cyclodextrins from Molecular Dynamics Simulations

Atomistic molecular dynamics (MD) simulations of α-, β-, and γ-cyclodextrins (ACD, BCD, and GCD) in aqueous solutions have been performed. Detailed analyses were carried out to compare the microscopic properties of water confined within the cavities of these macromolecules and in the hydration layers around them. It is noticed that reduced tetrahedral ordering of water in and around the CD molecules are associated with their restricted motions. Interestingly, unlike the translational motions, the rotational motions of cavity water molecules are found to be highly dependent on cavity dimensions. Additionally, it is found that severely hindered rotational motion of cavity water molecules is the origin of drastically restricted structural relaxation of hydrogen bonds involving those water molecules. It is demonstrated that the geometrical constraints within the cavities of the CD molecules enhance the rate of reformation of broken hydrogen bonds, thereby resulting in rapid establishment of the breaking and reformation equilibria for hydrogen bonds involving cavity water molecules.

Coupling between hydration layer dynamics and unfolding kinetics of HP-36.

We have performed atomistic molecular dynamics simulations of aqueous solutions of HP-36 at 300 K in its native state, as well as at high temperatures to explore the unfolding dynamics of the protein and its correlation with the motion of water around it. On increasing the temperature a partially unfolded molten globule state is formed where the smallest alpha helix (helix 2) unfolds into a coil. It is observed that the unfolding is initiated around the residue Phe-18 which shows a sharp displacement during unfolding. We have noticed that the unfolding of the protein affects the density of water near the protein surface. Besides, the dynamics of water in the protein hydration layer has been found to be strongly correlated with the time evolution of the unfolding process. We have introduced and calculated a displacement time correlation function to monitor the change in water motion relative to the protein backbone during unfolding. We find that the unfolding of helix 2 is associated with an increase in mobility of water around it as compared to water around the other two helices. We have also explored the microscopic aspects of secondary structure specific and site specific solvation dynamics of the protein. The calculations reveal that unfolding influences the solvation dynamics of the protein molecule in a heterogeneous manner depending on the location of the polar probe residues. This seems to be in agreement with recent experimental findings.

Excess entropy and crystallization in Stillinger-Weber and Lennard-Jones fluids

Molecular dynamics simulations are used to contrast the supercooling and crystallization behaviour of monatomic liquids that exemplify the transition from simple to anomalous, tetrahedral liquids. As examples of simple fluids, we use the Lennard-Jones (LJ) liquid and a pair-dominated Stillinger-Weber liquid (SW16). As examples of tetrahedral, water-like fluids, we use the Stillinger-Weber model with variable tetrahedrality parameterized for germanium (SW20), silicon (SW21), and water (SW(23.15) or mW model). The thermodynamic response functions show clear qualitative differences between simple and water-like liquids. For simple liquids, the compressibility and the heat capacity remain small on isobaric cooling. The tetrahedral liquids in contrast show a very sharp rise in these two response functions as the lower limit of liquid-phase stability is reached. While the thermal expansivity decreases with temperature but never crosses zero in simple liquids, in all three tetrahedral liquids at the studied pressure, there is a temperature of maximum density below which thermal expansivity is negative. In contrast to the thermodynamic response functions, the excess entropy on isobaric cooling does not show qualitatively different features for simple and water-like liquids; however, the slope and curvature of the entropy-temperature plots reflect the heat capacity trends. Two trajectory-based computational estimation methods for the entropy and the heat capacity are compared for possible structural insights into supercooling, with the entropy obtained from thermodynamic integration. The two-phase thermodynamic estimator for the excess entropy proves to be fairly accurate in comparison to the excess entropy values obtained by thermodynamic integration, for all five Lennard-Jones and Stillinger-Weber liquids. The entropy estimator based on the multiparticle correlation expansion that accounts for both pair and triplet correlations, denoted by S(trip), is also studied. S(trip) is a good entropy estimator for liquids where pair and triplet correlations are important such as Ge and Si, but loses accuracy for purely pair-dominated liquids, like LJ fluid, or near the crystallization temperature (T(thr)). Since local tetrahedral order is compatible with both liquid and crystalline states, the reorganisation of tetrahedral liquids is accompanied by a clear rise in the pair, triplet, and thermodynamic contributions to the heat capacity, resulting in the heat capacity anomaly. In contrast, the pair-dominated liquids show increasing dominance of triplet correlations on approaching crystallization but no sharp rise in either the pair or thermodynamic heat capacities.