Coarse-grained protein molecular dynamics simulations

A limiting factor in biological science is the time-scale gap between experimental and computational trajectories. At this point, all-atom explicit solvent molecular dynamics (MD) are clearly too expensive to explore long-range protein motions and extract accurate thermodynamics of proteins in isolated or multimeric forms. To reach the appropriate time scale, we must then resort to coarse graining. Here we couple the coarse-grained OPEP model, which has already been used with activated methods, to MD simulations. Two test cases are studied: the stability of three proteins around their experimental structures and the aggregation mechanisms of the Alzheimer's Abeta16-22 peptides. We find that coarse-grained isolated proteins are stable at room temperature within 50 ns time scale. Based on two 220 ns trajectories starting from disordered chains, we find that four Abeta16-22 peptides can form a three-stranded beta sheet. We also demonstrate that the reptation move of one chain over the others, first observed using the activation-relaxation technique, is a kinetically important mechanism during aggregation. These results show that MD-OPEP is a particularly appropriate tool to study qualitatively the dynamics of long biological processes and the thermodynamics of molecular assemblies.     

Potential energy surfaces and dynamics of Ni2+ ion aqueous solution: molecular dynamics simulation of the electronic absorption spectrum

We develop a model effective Hamiltonian for describing the electronic structures of first-row transition metals in aqueous solutions using a quasidegenerate perturbation theory. All the states consisting of 3d(n) electronic configurations are determined by diagonalizing a small effective Hamiltonian matrix, where various intermolecular interaction terms such as the electrostatic, polarization, exchange, charge transfer, and three-body interactions are effectively incorporated. This model Hamiltonian is applied to constructing the ground and triplet excited states potential energy functions of Ni(2+) in aqueous solution, based on the ab initio multiconfiguration quasidegenerate perturbation theory calculations. We perform molecular dynamics simulation calculations for the ground state of Ni(2+) aqueous solution to calculate the electronic absorption spectral shape as well as the ground state properties. Agreement between the simulation and experimental spectra is satisfactory, indicating that the present model can well describe the Ni(2+) excited state potential surfaces in aqueous solution.     

Accelerated molecular dynamics simulations of protein folding

Folding of four fast‐folding proteins, including chignolin, Trp‐cage, villin headpiece and WW domain, was simulated via accelerated molecular dynamics (aMD). In comparison with hundred‐of‐microsecond timescale conventional molecular dynamics (cMD) simulations performed on the Anton supercomputer, aMD captured complete folding of the four proteins in significantly shorter simulation time. The folded protein conformations were found within 0.2–2.1 Å of the native NMR or X‐ray crystal structures. Free energy profiles calculated through improved reweighting of the aMD simulations using cumulant expansion to the second‐order are in good agreement with those obtained from cMD simulations. This allows us to identify distinct conformational states (e.g., unfolded and intermediate) other than the native structure and the protein folding energy barriers. Detailed analysis of protein secondary structures and local key residue interactions provided important insights into the protein folding pathways. Furthermore, the selections of force fields and aMD simulation parameters are discussed in detail. Our work shows usefulness and accuracy of aMD in studying protein folding, providing basic references in using aMD in future protein‐folding studies. © 2015 Wiley Periodicals, Inc.     

Recent developments in molecular dynamics simulations of fluorescent membrane probes

Due to their sensitivity and versatility, the use of fluorescence techniques in membrane biophysics is widespread. Because membrane lipids are non-fluorescent, extrinsic membrane probes are widely used. However, the behaviour of these probes when inserted in the bilayer is often poorly understood, and it can be hard to distinguish between legitimate membrane properties and perturbation resulting from probe incorporation. Atomistic molecular dynamics simulations present a convenient way to address these issues and have been increasingly used in recent years in this context. This article reviews the application of molecular dynamics to the study of fluorescent membrane probes, focusing on recent work with complex design fluorophores and ordered bilayer systems.     

Excited state electronic structures and dynamics of NOCl: a new potential function set, absorption spectrum, and photodissociation mechanism

A set of analytical potential energy surfaces (PESs) for six singlet excited states of NOCl are constructed based on multireference configuration interaction calculations. The total absorption cross section at the energy range of 2-7 eV is calculated by quantum dynamics calculations with the present PESs and transition dipole moments. The calculated absorption spectrum agrees well with the experiment. It is also found that the A band with the absorption maximum at 6.3 eV is attributed to the transition to the 4 1A' state, though the excitations to the 3 1A' and 3 1A" states contribute to the spectrum at the energy range between 4 and 5 eV. The spin-forbidden transitions are concluded to be negligibly weak. The mechanism of photodissociation reaction at the energy region corresponding to the A band is examined. The nonadiabatic transition rates from the 4 1A' state to lower singlet and triplet states are estimated by Fermi's golden rule, and the transitions to the 1 1A' and 3 1A' states induced by vibronic coupling are found to be the predominant dissociation pathways. The experimentally observed energy dependence of the recoil anisotropy of the fragments is discussed based on the calculated nonadiabatic transition rates.     

Modern protein force fields behave comparably in molecular dynamics simulations

Several molecular dynamics simulations were performed on three proteins--bovine apo-calbindin D9K, human interleukin-4 R88Q mutant, and domain IIA of bacillus subtilis glucose permease--with each of the AMBER94, CHARMM22, and OPLS-AA force fields as implemented in CHARMM. Structural and dynamic properties such as solvent-accessible surface area, radius of gyration, deviation from their respective experimental structures, secondary structure, and backbone order parameters are obtained from each of the 2-ns simulations for the purpose of comparing the protein portions of these force fields. For one of the proteins, the interleukin-4 mutant, two independent simulations were performed using the CHARMM22 force field to gauge the sensitivity of some of these properties to the specific trajectory. In general, the force fields tested performed remarkably similarly with differences on the order of those found for the two independent trajectories of interleukin-4 with CHARMM22. When all three proteins are considered together, no force field showed any consistent trend in variations for most of the properties monitored in the study.     

Unbinding of nicotine from the acetylcholine binding protein: steered molecular dynamics simulations

The ligand binding/unbinding process is critical to our understanding of the pharmacology of both the nicotinic acetylcholine receptor (nAChR) and the acetylcholine binding protein (AChBP). Steered molecular dynamics simulations were performed to learn about the unbinding process of the full agonist nicotine. Three different pulling models were designed to investigate the possible binding/unbinding pathways: radial and tangent models, and also a mixed model. Of the three, the tangent pulling model finally failed to dissociate nicotine from the ligand binding pocket. The efficiency of the pulling force profiles was superior, and the opening of the C-loop was smaller in the mixed pulling model than that in the radial model. The most favorable pathway for the cholinergic agonist nicotine to enter or leave the binding pocket is through the principal binding side, following a curvilinear track. Noticeably, it has been seen that the unbinding of the nicotine is concomitant with a global rotation of the protein-ligand complex which could be caused by the interactions of the ligand with protein at the tangent direction.     

Experimental resolution of early steps in protein folding: testing molecular dynamics simulations

Time-resolved Tyr fluorescence spectroscopy coupled with a laser-induced temperature-jump (T-jump) was employed to follow the folding relaxation dynamics of the B-domain of Staphylococcal protein A. The single Tyr is located in helix 1 (H1) and is a sensitive probe of the structure of this helix and the overall helical bundle structure. The results from this study were compared to those from a complementary infrared T-jump study on this protein [Vu, D. M.; Myers, J. K.; Oas, T. G.; Dyer, R. B. Biochemistry 2004, 43, 3582]. Both methods detect a microsecond process that follows the cooperative relaxation of the helical bundle core. However, a fast process (10-7 s) that follows the relaxation of the individual helices was observed only with the infrared probe. Thus, fast formation of H1 is not observed, but rather H1 forms in the microsecond phase, concomitantly with the docking to (and stabilization by) the other two helices to form the helical bundle structure. This observation validates the results of several previous molecular dynamics simulations that predict H1 formation only in the final assembly of the helix bundle.     

Multibaric-multithermal ensemble molecular dynamics simulations

We present new generalized-ensemble molecular dynamics simulation algorithms, which we refer to as the multibaric-multithermal molecular dynamics. We describe three algorithms based on (1) the Nosé thermostat and the Andersen barostat, (2) the Nosé-Poincaré thermostat and the Andersen barostat, and (3) the Gaussian thermostat and the Andersen barostat. The multibaric-multithermal simulations perform random walks widely both in the potential-energy space and in the volume space. Therefore, one can calculate isobaric-isothermal ensemble averages in wide ranges of temperature and pressure from only one simulation run. We test the effectiveness of the multibaric-multithermal algorithm by applying it to a Lennard-Jones 12-6 potential system.     

The influence of aqueous versus glassy solvents on protein dynamics: vibrational echo experiments and molecular dynamics simulations

Spectrally resolved infrared stimulated vibrational echo measurements are used to measure the vibrational dephasing of the CO stretching mode of carbonmonoxy-hemoglobin (HbCO), a myoglobin mutant (H64V), and a bacterial cytochrome c(552) mutant (Ht-M61A) in aqueous solution and trehalose glasses. The vibrational dephasing of the heme-bound CO is significantly slower for all three proteins embedded in trehalose glasses compared to that of aqueous protein solutions. All three proteins exhibit persistent but notably slower spectral diffusion when the protein surface is fixed by the glassy solvent. Frequency-frequency correlation functions (FFCFs) of the CO are extracted from the vibrational echo data to reveal that the structural dynamics, as sensed by the CO, of the three proteins in trehalose and aqueous solution are dominated by fast (tens of femtoseconds), motionally narrowed fluctuations. MD simulations of H64V in dynamic and "static" water are presented as models of the aqueous and glassy environments. FFCFs are calculated from the H64V simulations and qualitatively reproduce the important features of the experimentally extracted FFCFs. The suppression of long time scale (picoseconds to tens of picoseconds) frequency fluctuations (spectral diffusion) in the glassy solvent is the result of a damping of atomic displacements throughout the protein structure and is not limited to structural dynamics that occur only at the protein surface. The analysis provides evidence that some dynamics are coupled to the hydration shell of water, supporting the idea that the bioprotection offered by trehalose is due to its ability to immobilize the protein surface through a thin, constrained layer of water.     

Potential energy landscape of the photoinduced multiple proton-transfer process in the green fluorescent protein: classical molecular dynamics and multiconfigurational electronic structure calculations

The green fluorescent protein proton wire operating upon photoexcitation of the internally caged chromophore is investigated by means of classical molecular dynamics and multiconfigurational electronic structure calculations. The structure of the proton wire is studied for the solvated protein, showing that the wire is likely to be found in a configuration ready to operate as soon as the chromophore is photoexcited, and leading to a total of three proton translocations in the vicinity of the chromophore. Multiconfigurational CASSCF and CASPT2 calculations provide a detailed overview of the energy landscape of the proton wire for the ground electronic state S0, the photoactive 1pi pi* state, and the charge-transfer 1pi sigma* state. The results allow discussion of the operation of the wire in terms of the sequence of proton-transfer events and the participation of each electronic state.     

Phonostat: thermostatting phonons in molecular dynamics simulations

Thermostat algorithms in a molecular dynamics simulation maintain an average temperature of a system by regulating the atomic velocities rather than the internal degrees of freedom. Herein, we present a "phonostat" algorithm that can regulate the total energy in a given internal degree of freedom. In this algorithm, the modal energies are computed at each time step using a mode-tracking scheme and then the system is driven by an external driving force of desired frequency and amplitude. The rate and amount of energy exchange between the phonostat and the system is controlled by two distinct damping parameters. Two different schemes for controlling the external driving force amplitude are also presented. In order to test our algorithm, the method is applied initially to a simple anharmonic oscillator for which the role of various phonostat parameters can be carefully tested. We then apply the phonostat to a more realistic (10,0) carbon nanotube system and show how such an approach can be used to regulate energy of highly anharmonic modes.     

Energetics and dynamics in MbCN: CN--vibrational relaxation from molecular dynamics simulations

The dynamics of the cyanide anion bound to sperm-whale myoglobin is investigated using atomistic simulations. With density-functional theory, a 2D potential energy surface for the cyanide-heme complex is calculated. Two deep minima with a stabilization energy of approximately 50 kcal/mol corresponding to two different binding orientations (Fe-CN and Fe-NC) of the ligand are found. The Fe-CN conformation is favored over Fe-NC by several kcal/mol. Mixed quantum mechanics/molecular mechanics calculations show that the binding orientation affects the bond strength of the ligand, with a significantly different bond length and a 25 cm-1 shift in the fundamental CN-frequency. For the molecular dynamics (MD) simulations, a 3-center fluctuating charge model for the Fe-CN unit is developed that captures polarization and ligand-metal charge transfer. Stability arguments based on the energetics around the active site and the CN- frequency shifts suggest that the Fe-CN conformation with epsilon-protonation of His epsilon 64 are most likely, which is in agreement with experiment. Both equilibrium and nonequilibrium MD simulations are carried out to investigate the relaxation time scale and possible relaxation pathways in bound MbCN. The nonequilibrium MD simulations with a vibrationally excited ligand reveal that vibrational relaxation takes place on a time scale of hundreds of picoseconds within the active site. This finding supports the hypothesis that the experimentally observed relaxation rate (3.6 ps) reflects the repopulation of the electronic ground state.     

Phenol-benzene complexation dynamics: quantum chemistry calculation, molecular dynamics simulations, and two dimensional IR spectroscopy

Molecular dynamics (MD) simulations and quantum mechanical electronic structure calculations are used to investigate the nature and dynamics of the phenol-benzene complex in the mixed solvent, benzene/CCl4. Under thermal equilibrium conditions, the complexes are continuously dissociating and forming. The MD simulations are used to calculate the experimental observables related to the phenol hydroxyl stretching mode, i.e., the two dimensional infrared vibrational echo spectrum as a function of time, which directly displays the formation and dissociation of the complex through the growth of off-diagonal peaks, and the linear absorption spectrum, which displays two hydroxyl stretch peaks, one for the complex and one for the free phenol. The results of the simulations are compared to previously reported experimental data and are found to be in quite reasonable agreement. The electronic structure calculations show that the complex is T shaped. The classical potential used for the phenol-benzene interaction in the MD simulations is in good accord with the highest level of the electronic structure calculations. A variety of other features is extracted from the simulations including the relationship between the structure and the projection of the electric field on the hydroxyl group. The fluctuating electric field is used to determine the hydroxyl stretch frequency-frequency correlation function (FFCF). The simulations are also used to examine the number distribution of benzene and CCl4 molecules in the first solvent shell around the phenol. It is found that the distribution is not that of the solvent mole fraction of benzene. There are substantial probabilities of finding a phenol in either a pure benzene environment or a pure CCl4 environment. A conjecture is made that relates the FFCF to the local number of benzene molecules in phenol's first solvent shell.     

Comparison between self-guided Langevin dynamics and molecular dynamics simulations for structure refinement of protein loop conformations

This article presents a comparative analysis of two replica‐exchange simulation methods for the structure refinement of protein loop conformations, starting from low‐resolution predictions. The methods are self‐guided Langevin dynamics (SGLD) and molecular dynamics (MD) with a Nosé–Hoover thermostat. We investigated a small dataset of 8‐ and 12‐residue loops, with the shorter loops placed initially from a coarse‐grained lattice model and the longer loops from an enumeration assembly method (the Loopy program). The CHARMM22 + CMAP force field with a generalized Born implicit solvent model (molecular‐surface parameterized GBSW2) was used to explore conformational space. We also assessed two empirical scoring methods to detect nativelike conformations from decoys: the all‐atom distance‐scaled ideal‐gas reference state (DFIRE‐AA) statistical potential and the Rosetta energy function. Among the eight‐residue loop targets, SGLD out performed MD in all cases, with a median of 0.48 Å reduction in global root‐mean‐square deviation (RMSD) of the loop backbone coordinates from the native structure. Among the more challenging 12‐residue loop targets, SGLD improved the prediction accuracy over MD by a median of 1.31 Å, representing a substantial improvement. The overall median RMSD for SGLD simulations of 12‐residue loops was 0.91 Å, yielding refinement of a median 2.70 Å from initial loop placement. Results from DFIRE‐AA and the Rosetta model applied to rescoring conformations failed to improve the overall detection calculated from the CHARMM force field. We illustrate the advantage of SGLD over the MD simulation model by presenting potential‐energy landscapes for several loop predictions. Our results demonstrate that SGLD significantly outperforms traditional MD in the generation and populating of nativelike loop conformations and that the CHARMM force field performs comparably to other empirical force fields in identifying these conformations from the resulting ensembles. Published 2011 Wiley Periodicals, Inc. J Comput Chem, 2011     

Vesicle shapes from molecular dynamics simulations

Lipid bilayer membranes are known to form various structures such as large sheets or vesicles. When the two leaflets of the bilayer have an equal composition, the membrane preferentially forms a flat sheet or a spherical vesicle. However, a difference in the composition of the two leaflets may result in a curved bilayer or in a wide variety of vesicle shapes. Vesicles with different shapes have already been shown in experiments and diverse vesicle shapes have been predicted theoretically from energy minimization of continuous curves. Here we present a molecular dynamics study of the effect of small changes in the phospholipid headgroups on the spontaneous curvature of the bilayer and on the resulting vesicle shape transformations. Small asymmetries in the bilayers already result in high spontaneous curvature and large vesicle deformations. Vesicle shapes that are formed include ellipsoids, discoids, pear-shaped vesicles, cup-shaped vesicles, as well as budded vesicles. Comparison of these vesicles with theoretically derived vesicle shapes shows both resemblances and differences.     

On simulations of complex interfaces: molecular dynamics simulations of stationary phases

Methodological considerations for molecular dynamics simulations of complex interfaces are presented in this article. A slab geometry is examined in the context of stationary phases where selectivity occurs predominantly in pores within silica beads. Specifically, we examine the Whelk-O1 interface with n-hexane/2-propanol, the TMA-(Pro)(2)-N(CH(3))-tether interface with n-hexane/2-propanol, and the C(18)H(37)Si interface with water/methanol. The following methodological issues are considered in detail: The assessment of solvent density within the confined region and excluded volume of the interface; the structural equilibration of surface-bound moieties; solvent equilibration for binary mixtures; surface size effects, and periodic boundary conditions; the treatment of electrostatic interactions; and the impact of pore size.     

Myoglobin-CO substate structures and dynamics: multidimensional vibrational echoes and molecular dynamics simulations

Spectrally resolved infrared stimulated vibrational echo data were obtained for sperm whale carbonmonoxymyoglobin (MbCO) at 300 K. The measured dephasing dynamics of the CO ligand are in agreement with dephasing dynamics calculated with molecular dynamics (MD) simulations for MbCO with the residue histidine-64 (His64) having its imidazole epsilon nitrogen protonated (N(epsilon)-H). The two conformational substate structures B(epsilon) and R(epsilon) observed in the MD simulations are assigned to the spectroscopic A(1) and A(3) conformational substates of MbCO, respectively, based on the agreement between the experimentally measured and calculated dephasing dynamics for these substates. In the A(1) substate, the N(epsilon)-H proton and N(delta) of His64 are approximately equidistant from the CO ligand, while in the A(3) substate, the N(epsilon)-H of His64 is oriented toward the CO, and the N(delta) is on the surface of the protein. The MD simulations show that dynamics of His64 represent the major source of vibrational dephasing of the CO ligand in the A(3) state on both femtosecond and picosecond time scales. Dephasing in the A(1) state is controlled by His64 on femtosecond time scales, and by the rest of the protein and the water solvent on longer time scales.