The capabilities of the polarizable force fields for alchemical free energy calculations have been limited by the high computational cost and complexity of the underlying potential energy functions. In this work, we present a GPU-based general alchemical free energy simulation platform for polarizable potential AMOEBA. Tinker-OpenMM, the OpenMM implementation of the AMOEBA simulation engine has been modified to enable both absolute and relative alchemical simulations on GPUs, which leads to a similar to 200-fold improvement in simulation speed over a single CPU core. We show that free energy values calculated using this platform agree with the results of Tinker simulations for the hydration of organic compounds and binding of host-guest systems within the statistical errors. In addition to absolute binding, we designed a relative alchemical approach for computing relative binding affinities of ligands to the same host, where a special path was applied to avoid numerical instability due to polarization between the different ligands that bind to the same site. This scheme is general and does not require ligands to have similar scaffolds. We show that relative hydration and binding free energy calculated using this approach match those computed from the absolute free energy approach. (C) 2017 Wiley Periodicals, Inc.
Amyloid-beta peptide (A beta) fibrillation is pathologically associated with Alzheimer's disease (AD), and this has resulted in the development of an A beta inhibitor which is essential for the treatment of AD. However, the design of potent agents which can target upstream secretases, inhibit A beta toxicity and aggregation, as well as cross the blood-brain barrier remains challenging. In, this research carbon dots for AD treatment were investigated in vitro using experimental and computational methods for the first time. The results presented here demonstrate a novel strategy for the discovery of novel antiamyloidogenic agents for AD treatments.
Accurately measuring antibody repertoire sequence composition in a small amount of blood is challenging yet important for understanding repertoire responses to infection and vaccination. We develop molecular identifier clustering-based immune repertoire sequencing (MIDCIRS) and use it to study age-related antibody repertoire development and diversification before and during acute malaria in infants (<12 months old) and toddlers (12-47 months old) with 4-8ml of blood. Here, we show this accurate and high-coverage repertoire-sequencing method can use as few as 1000 naive B cells. Unexpectedly, we discover high levels of somatic hypermutation in infants as young as 3 months old. Antibody clonal lineage analysis reveals that somatic hypermutation levels are increased in both infants and toddlers upon infection, and memory B cells isolated from individuals who previously experienced malaria continue to induce somatic hypermutations upon malaria rechallenge. These results highlight the potential of antibody repertoire diversification in infants and toddlers.
Aromatic molecules with pi electrons are commonly involved in chemical and biological recognitions. For example, nucleobases play central roles in DNA/RNA structure and their interactions with proteins. The delocalization of the pi electrons is responsible for the high polarizability of aromatic molecules. In this work, the AMOEBA force field has been developed and applied to 5 regular nucleobases and 12 aromatic molecules. The permanent electrostatic energy is expressed as atomic multipole interactions between atom pairs, and many-body polarization is accounted for by mutually induced atomic dipoles. We have systematically investigated aromatic ring stacking and aromatic-water interactions for nucleobases and aromatic molecules, as well as base-base hydrogen-bonding pair interactions, all at various distances and orientations. van der Waals parameters were determined by comparison to the quantum mechanical interaction energy of these dimers and fine-tuned using condensed phase simulation. By comparing to quantum mechanical calculations, we show that the resulting classical potential is able to accurately describe molecular polarizability, molecular vibrational frequency, and dimer interaction energy of these aromatic systems. Condensed phase properties, including hydration free energy, liquid density, and heat of vaporization, are also in good overall agreement with experimental values. The structures of benzene liquid phase and benzene-water solution were also investigated by simulation and compared with experimental and PDB structure derived statistical results.
We introduce a new class of methods, denoted as Truncated Conjugate Gradient(TCG), to solve the many-body polarization energy and its associated forces in molecular simulations (i.e. molecular dynamics (MD) and Monte Carlo). The method consists in a fixed number of Conjugate Gradient (CG) iterations. TCG approaches provide a scalable solution to the polarization problem at a user-chosen cost and a corresponding optimal accuracy. The optimality of the CG-method guarantees that the number of the required matrix-vector products are reduced to a minimum compared to other iterative methods. This family of methods is non-empirical, fully adaptive, and provides analytical gradients, avoiding therefore any energy drift in MD as compared to popular iterative solvers. Besides speed, one great advantage of this class of approximate methods is that their accuracy is systematically improvable. Indeed, as the CG-method is a Krylov subspace method, the associated error is monotonically reduced at each iteration. On top of that, two improvements can be proposed at virtually no cost: (i) the use of preconditioners can be employed, which leads to the Truncated Preconditioned Conjugate Gradient (TPCG); (ii) since the residual of the final step of the CG-method is available, one additional Picard fixed point iteration ("peek"), equivalent to one step of Jacobi Over Relaxation (JOR) with relaxation parameter omega, can be made at almost no cost. This method is denoted by TCG-n(omega). Black-box adaptive methods to find good choices of omega are provided and discussed. Results show that TPCG-3(omega) is converged to high accuracy (a few kcal/mol) for various types of systems including proteins and highly charged systems at the fixed cost of four matrix-vector products: three CG iterations plus the initial CG descent direction. Alternatively, T(P)CG-2(omega) provides robust results at a reduced cost (three matrix-vector products) and offers new perspectives for long polarizable MD as a production algorithm. The T(P)CG-1(omega) level provides less accurate solutions for inhomogeneous systems, but its applicability to well-conditioned problems such as water is remarkable, with only two matrix-vector product evaluations.
This work presents a systematic development of a new van der Waals potential (vdW2016) for common organic molecules based on symmetry-adapted perturbation theory (SAPT) energy decomposition. The Buf-14-7 function, as well as Cubic-mean and Waldman-Hagler mixing rules were chosen given their best performance among other popular potentials. A database containing 39 organic molecules and 108 dimers was utilized to derive a general set of vdW parameters, which were further validated on nucleobase stacking systems and testing organic dimers. The vdW2016 potential is anticipated to significantly improve the accuracy and transferability of new generations of force fields for organic molecules.
Diffusion of transmembrane and peripheral membrane-bound proteins within the crowded cellular membrane environment is essential to diverse biological processes including cellular signaling, endocytosis, and motility. Nonetheless we presently lack a detailed understanding of the influence of physiological levels of crowding on membrane protein diffusion. Utilizing quantitative in vitro measurements, here we demonstrate that the diffusivities of membrane bound proteins follow a single linearly decreasing trend with increasing membrane coverage by proteins. This trend holds for homogenous protein populations across a range of protein sizes and for heterogeneous mixtures of proteins of different sizes, such that protein diffusivity is controlled by the total coverage of the surrounding membrane. These results demonstrate that steric exclusion within the crowded membrane environment can fundamentally limit the diffusive rate of proteins, regardless of their size. In cells this "speed limit" could be modulated by changes in local membrane coverage, providing a mechanism for tuning the rate of molecular interaction and assembly.
We propose a general coupling of the Smooth Particle Mesh Ewald SPME approach for distributed multipoles to a short-range charge penetration correction modifying the charge-charge, charge-dipole and charge-quadrupole energies. Such an approach significantly improves electrostatics when compared to ab initio values and has been calibrated on Symmetry-Adapted Perturbation Theory reference data. Various neutral molecular dimers have been tested and results on the complexes of mono- and divalent cations with a water ligand are also provided. Transferability of the correction is adressed in the context of the implementation of the AMOEBA and SIBFA polarizable force fields in the TINKER-HP software. As the choices of the multipolar distribution are discussed, conclusions are drawn for the future penetration-corrected polarizable force fields highlighting the mandatory need of non-spurious procedures for the obtention of well balanced and physically meaningful distributed moments. Finally, scalability and parallelism of the short-range corrected SPME approach are addressed, demonstrating that the damping function is computationally affordable and accurate for molecular dynamics simulations of complex bio- or bioinorganic systems in periodic boundary conditions.