Mark Tuckerman
New York University

One of the computational grand challenge problems is the development of methodology capable of sampling conformational equilibria in systems characterized by rough energy landscapes.  If met, many important problems, most notably biomolecular structure prediction and the discovery of the polymorphism in organic molecular crystals could be significantly impacted.  In this talk, I will discuss new approaches for enhancing sampling and mapping out the free energy landscape of systems described by rough potential energy surfaces.  The new techniques are based on a molecular dynamics calculation in which a set of pre-selected collective variables (CVs) is singled out for enhanced sampling.  The enhancement is achieved by applying a high temperature to the CVs and decoupling them adiabatically from the remaining degrees of freedom.  This framework also allows incorporation of bias potentials for increased efficiency and will be shown to outperform popular approaches such as metadynamics.  Application of an isobaric version of the method to organic molecular crystals such as benzene and naphthalene allows all of the known polymorphs to be identified from a short simulation.  I will demonstrate the performance of a biased version of the enhanced sampling approach by generating the conformational equilibria of a number of small polypeptides.  Finally, I will discuss a new multi-scale approach, employing gentlest ascent dynamics and stochastic relaxation, for rapidly locating minima and saddle points on the free energy landscape.  Such an approach leads directly to a graph-based representation of high-dimensional free energy surfaces.

Dongqing WEI
Shanghai Jiaotong University

Techniques of rare event dynamics were improved[1] and implemented along with biochemical simulation packages. Charged methyl guanidine is used as a model ion to study the transmembrane permeation of ions. With a widely applied reaction coordinate, our umbrella sampling discovers a dilemma in obtaining the transition trajectory and the potential of mean force — significant finite-size effect in small systems and serious hysteresis in large systems. This suggests the importance of
re-examining the validity of the transition trajectory and the potential of mean force obtained in previous works. In this work, a novel reaction coordinate is designed to acquire a continuous trajectory of the permeation process in a large simulation system. This continuous trajectory demonstrates the presence of a water pore at the saddle state which is not clearly observed in previous works. With the presence of the water pore, the energy barrier is shown to be significantly decreased.
Applications were made to study biological systems with relevance to drug design and drug metabolism. The rare event dynamics simulations were performed to understand the kinetic and thermodynamic free energy information on the drug binding sites in the M2 proton channel. Our results give a theoretical framework to interpret and reconcile existing and often conflicting results regarding these two binding sites, thus helping to expand our understanding of M2 drug binding, and may help guide the design and screening of novel drugs to combat the virus (JACS, 133, 10817 (2011))[2].
A new agonist of a membrane protein, α7nAChR was discovered with above mentioned simulation technology[3-7], i.e., wgx50, which was tested in vitro experiments that it could combine with α7nAChR on nerve cells, induce depolymerization of Aβ, inhibit Aβ-induced neurocyte apoptosis, and suppress the release of TNF-αand IL-1β from microglia. In vivo experiments showed that it could improve the cognition ability in APP-Transgenic Mice. These results suggest that wgx50 is a promising drug candidate for AD treatment.

References:
1.    Yukun Wang, Dan Hu and Dong-Qing Wei, “Transmembrane Permeation Mechanism of Charged Methyl Guanidine”, J. Chem. Theory Comput., 10 (4), 1717–1726(2014).
2.    Ruo Xu Gu, Limin Angela Liu and Dong Qing Wei,(2011) J. Am. Chem. Soc. 133 (28) 10817–10825.
3.    H. R. Arias, Ruo-Xu Gu, Dominik Feuerbach, Bao-Bao Guo, Yong Ye, and D.Q. Wei*, “Novel Positive Allosteric Modulators of the Human α7 Nicotinic  Acetylcholine Receptor”, Biochemistry,  50, 5263–5278(2011).
4.    Peng Lian, Dong-Qing Wei*, Jing-Fang Wang*, Kuo-Chen Chou,  “An Allosteric Mechanism Inferred from Molecular Dynamics Simulations on Phospholamban Pentamer in Lipid Membranes”, PLoS ONE ,  6,  e18587(2011).
5.    Hugo R. Arias*, Ruo-Xu Gu,  Dominik Feuerbach,and Dong-Qing Wei, “Different interaction between the agonist JN403 and the competitive antagonist methyllycaconitine with the human alpha7 nicotinic acetylcholine receptor”, Biochemistry, 49, 4169-4180(2010).
6.    Maoping Tang, Zhaoxia Wang, Ying Zhou, Wangjie Xu, Shengtian Li,Lianyun Wang, Dong-Qing Wei*, Zhongdong Qiao*, “A novel drug candidate for Alzheimer disease treatment - gx-50 derived from Zanthoxylum Bungeanum”, J. Alzheimer’s Disease, 34, 203–213 (2013).

Zhigang SHUAI
Tsinghua University

We have implemented the nonadiabatic Ehrenfest dynamics within the density functional tight binding (DFTB) framework to investigate the carrier transport in the donor-acceptor type photovoltaic polymers. The equations of motion for the electrons are evolved under the fixed subspace spanned by the active molecular orbitals during each nuclear time step and the feedback from charge to the nuclei motions, namely, the polaronic effect is considered. We investigated the charge transport dynamics for the ladder-type poly(p-phenylenes) (LPPP) and poly(diketopyrrolo-pyrrole (DPP)) series with ~2×10³ atoms. It was found that the diffusion abilities are determined by the magnitude of transfer integrals and localization length for frontier orbital which caused by the self-trapping effects (polaron) arising from the double bond stretching and twisting motions. This method can be useful in exploring the underlying charge transport behavior and improving the structure design of materials in organic electronics.

Jinlong YANG
University of Science and Technology of China

As an ultimate clean energy, hydrogen produced by photocatalytic water splitting using solar energy plays an important role in solving energy and environmental problems. The key of solar hydrogen production is to develop photocatalysts active under visible light. Traditional photocatalysts are discovered in metal oxides, sulfides and nitrides with d0 or d10 transition metal cations. Unfortunately, most of these catalysts are active only under UV irradiation, while others absorbing visible light either suffer stability problems during the reaction process, such as photocorrosion for metal sulfide photocatalyst, or the quantum yield is too low for practical use. Photocatalysts with sufficiently high productivity are not found yet. Searching for new efficient photocatalysts both from theoretical and experimental aspects is urgently needed.
Metal-free photocatalysts may have the advantage of non-toxicity and good processability, and are gradually becoming an important catalyst developing. In this report, based on first principles calculations, we propose two visible light driven metal-free photocatalysts for water splitting by chemical functionazation of BN sheet and germanane, that is, half-hydrogenated BN nanosheet (H-BN) with a band gap of 2.24eV and fluorine substituted germanane (GeH2-xFx) with a gap of 1.45eV. We find that the conditions for water splitting are well satisfied and the photocatalysts possess a good electron-hole separation.

Xiao HE
East China Normal University

Routine quantum mechanical (QM) calculation on macromolecules is still a formidable task in computational chemistry and biology. The major computational limitation of QM methods is the scaling problem, since the cost of ab initio calculation scales n-th power or even worse with the system size. In the past decade, the fragmentation approach based on the chemical locality has become one of the central focuses in developing linear-scaling QM method for large systems. The attractive aspect of fragmentation approach is that it can be highly parallelized on massive computer nodes and also applied to all levels of ab initio electronic structure theories with a minimum of development efforts. 
In my talk, two fragmentation methods and their applications to macromolecules will be discussed. They are the electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method and automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) approach. The EE-GMFCC method is developed from the MFCC approach, which was initially aimed to obtain accurate protein-ligand QM interaction energy. By introducing the electrostatic embedding field in each fragment calculation and two-body interaction energy correction on top of the MFCC approach, the EE-GMFCC method is capable of accurately reproducing the QM molecular properties (such as the dipole moment, electron density and electrostatic potential), total energy and electrostatic solvation energy from full system calculations for proteins.
On the other hand, the AF-QM/MM was aimed for efficient QM calculation of protein NMR parameters including chemical shift, chemical shift anisotropy tensor and spin-spin coupling constant. In the AF-QM/MM approach, each amino acid and all the residues in its vicinity are automatically assigned as the QM region through a distance cutoff for each residue-centric QM/MM calculation. Local chemical properties of central residue can be obtained from individual QM/MM calculation. The AF-QM/MM approach precisely reproduces the NMR chemical shifts of proteins in gas phase from full system QM calculations. Furthermore, by incorporating implicit and explicit solvent models, the protein NMR chemical shifts calculated by the AF-QM/MM method are in excellent agreement with experimental values. The applications of the AF-QM/MM method may also be extended to more general biological systems such as DNA/RNA and protein-ligand complexes.

Xin XU
Fudan University

There remain major challenges in using density functional theory (DFT) to accurately predict some important chemical properties such as ionization potential (IP), electron affinity (EA) and their difference (i.e. fundamental band gap, Eg = IP – EA). The main problem of relating Kohn-Sham (KS) frontier orbital energies to these properties have been traced to the delocalization errors by Yang and co-workers,[1] because common approximate functionals exhibit a convex behaviour in violation of the exact linearity condition for fractional charges. It is not clear, however, how a new class of approximate functionals, namely doubly hybrid (DH) functionals, behaves in this situation. We present here such an analysis and show that the XYG3 type of DH functionals [2,3] give good agreement between the frontier orbital energies and the experimental IP, EA, and Eg, as expected from their nearly straight line fractional charge behaviors.

Xuhui HUANG
The Hong Kong University of Science and Technology

Simulating biologically relevant timescales at atomic resolution is a challenging task since typical atomistic simulations are at least two orders of magnitude shorter. Markov State Models (MSMs), a kinetic network model, built from molecular dynamics (MD) simulations provide one means of overcoming this gap without sacrificing atomic resolution by extracting long time dynamics from short MD simulations. In this talk, I will demonstrate the power of MSMs by applying it to simulate the complex conformational changes, that occurs at tens of microsecond timescales for a large molecular machine: the RNA polymerase complex for gene transcription (close to half million atoms). In the second part of my talk, I will introduce a new efficient dynamic clustering algorithm for the automatic construction of MSMs for multi-body systems. We have successfully applied this new algorithm to model the protein-ligand recognition and hydrophobic collapse processes that occur at a mixture of different timescales.

Zlatko Bačić
New York University

The behavior of hydrogen molecules inside nanoscale cavities of diverse host materials, e.g., fullerenes, carbon nanotubes, clathrate hydrates, and metal-organic frameworks, has received a great deal of attention in recent years. Much of the research has been driven by the potential which some of these systems have for hydrogen storage applications. In nanoscale confinement, the transnational motions of the caged molecules are quantized and strongly coupled to the molecular rotations, which are also quantized. I will review our rigorous quantum treatment of the intricate coupled translation-rotation (TR) dynamics of the caged H2/HD/D2, their dependence on the symmetry of the nanocavity, and the distinct spectroscopic signatures of the TR coupling that we have identified. These TR eigenstates are directly probed by the inelastic neutron scattering (INS) spectroscopy. Therefore, I will also present our recently developed methodology for accurate quantum simulation of the INS spectra of a hydrogen molecule in a nanocavity of an arbitrary shape, its implementation to H2/HD in clathrate hydrates, C60, and C70, and comparison with the measured INS spectra. A new and unexpected selection rule that we have derived for the INS spectroscopy of H2/HD in a near-spherical cage such as C60 will be highlighted. It explains why the INS transitions between certain TR eigenstates of H2/HD in C60 have zero intensity and do not appear in the spectra. Our theoretical predictions have been confirmed by the recently measured INS spectra of H2@C60, thus validating the selection rule - the first ever identified in INS spectroscopy.

Jiushu SHAO
Beijing Normal University

Upon employing the Hubbard-Stratonovich transformation or Ito calculus as well as the Girsanov transformation, the quantum dynamics of a dissipative system described by a system-plus-bath model is shown to satisfy a stochastic Liouville equation driven by complex noises, which might be regarded as the quantum analogue to the traditional Langevin equation.

The stochastic formulation can be used not only as a theoretical tool for deriving master equations for specific systems or developing approximations, but also as a practical technique for simulating nonequilibrium dynamics numerically via a direct implementation or transforming to a deterministic algorithm a la hierarchical equations. It has been demonstrated that a mixed random-deterministic scheme taking both advantages of the random and deterministic treatments is effective to calculate the zero-temperature dynamics of the spin-boson model with Ohmic dissipation. It is observed that for strong dissipation the population in the localized state obeys a simple rate dynamics and time scale is proportional to the reciprocal of the cutoff frequency.

Yijing YAN
The Hong Kong University of Science and Technology

Correlated system-bath coherence occurs whenever quantum nature of environment cannot be neglected. This is a type of quantum entanglement, which is playing ever increasing roles in many fields of science nowadays. In this talk, I will present a newly developed theory, the many-dissipaton density matrix formalism, for hybrid system and bath dynamics. With a quasi-particle picture for bath influence, this theory unifies the treatments on three distinct classes of environments, electron bath, phonon bath, and exciton (two-level spin) bath. Dynamical variables in formulation are no longer just the reduced density matrix for system, but remarkably also those for quasi-particles of hybridizing bath. The present formalism offers efficient and accurate means for the study of steady state (nonequilibrium and equilibrium) and real-time dynamical properties of both systems and hybridizing bath. It further provides universal evaluations, exact in principle, on various correlation functions, including even those of hybridizing bath degrees of freedom. Induced bath dynamics could be reflected directly in experimentally measurable quantities, such as Fano resonances and quantum transport current noise spectrum. Some benchmark evaluations on strongly correlated electronic systems will also be presented.

Yiqin GAO
Peking University

In cells, biological molecules function in an aqueous solution. Electrolytes and other small molecules play important roles in keeping the osmotic pressure of the cellular environment as well as the structure formation and function of biomolecules. More than a century ago Franz Hofmeister ranked the ions based on their salting-out ability on proteins. The series named after him was later found to be valid in salt effects on many other properties. The anionic Hofmeister series is generally written as CO32- > SO42-> F- > Cl- > Br- > I- ~ NO3-, with the ions on the left hand side called kosmotropes and those on the right hand side chaotropes. 
A simple theory was formulated for salt effects on water/air surface tension, which takes into account the interactions of individual ions with water. The theory was then extended to understand how salts and other small molecules affect protein backbone solvation and protein secondary structure formation, with ion binding to the amide and ion pairing included. The theory predicts that at low concentrations co-solutes rich in proton donors and those rich in proton acceptors have opposite effects and function as protein secondary structure denaturants and renaturants, respectively, consistent with experimental observations: Urea and Gdm+, two common denaturants, are both rich in hydrogen donors, and the increase of amide solvation by the denaturants again can be a result of both direct and indirect effects, the latter increases the free hydrogen bond donors of water.  In contrast, addition of molecules acting mainly as hydrogen acceptors, such as alcohols, GB, and TMAO desolvate the protein backbone and therefore enhance the secondary structure. MD simulations used to test these theoretical results will also be discussed.