Single molecule pulling with large time steps

Recently, we presented a generalisation of the Jarzynski non-equilibrium work theorem for phase space mappings. The formalism shows that one can determine free energy differences from approximate trajectories obtained from molecular dynamics simulations in which very large timesteps are used. In this work we test the method by simulating the force induced unfolding of a deca-alanine helix in vacuum. The excellent agreement between results obtained with a small, conservative time step of 0.5 fs and results obtained with a time step of 3.2 fs (i.e., close to the stability limit) indicates that the large time step approach is practical for such complex biomolecules. We further adapt the method of Hummer and Szabo for the simulation of single-molecule force spectroscopy experiments to the large time step method. While trajectories generated with large steps are approximate and may be unphysical - in the simulations presented here we observe a violation of the equipartition theorem - the computed free energies are exact in principle. In terms of efficiency, the optimum time step for the unfolding simulations lies in the range 1-3 fs.Comment: 8 pages, 8 figure

Gauge Independence of IR singularities in Non-Commutative QFT - and Interpolating Gauges

IR divergences of a non-commutative U(1) Maxwell theory are discussed at the one-loop level using an interpolating gauge to show that quadratic IR divergences are independent not only from a covariant gauge fixing but also independent from an axial gauge fixing.Comment: 11 pages, 2 figures, v1 minor correction

A Generalization of Slavnov-Extended Non-Commutative Gauge Theories

We consider a non-commutative U(1) gauge theory in 4 dimensions with a modified Slavnov term which looks similar to the 3-dimensional BF model. In choosing a space-like axial gauge fixing we find a new vector supersymmetry which is used to show that the model is free of UV/IR mixing problems, just as in the previously discussed model in arXiv:hep-th/0604154. Finally, we present generalizations of our proposed model to higher dimensions.Comment: 25 pages, no figures; v2 minor correction

CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed

Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published. They include the following: new faster simulation engines, accessible user interfaces for convenient workflows, and a vast array of simulation and analysis methods that encompass quantum mechanical, atomistic, and coarse-grained levels, as well as extensive coverage of force fields. In addition to providing the current snapshot of the CHARMM development, this review may serve as a starting point for exploring relevant theories and computational methods for tackling contemporary and emerging problems in biomolecular systems. CHARMM is freely available for academic and nonprofit research at https://academiccharmm.org/program

On analytical corrections for restraints in absolute binding free energy calculations

Double decoupling absolute binding free energy simulations require an intermediate state at which the ligand is held solely by restraints in a position and orientation resembling the bound state. One possible choice consists of one distance, two angle and three dihedral angle restraints. Here, I demonstrate that in practically all cases, the analytical correction derived under the rigid rotator harmonic oscillator approximation is sufficient to account for the free energy of the restraint

Use of Interaction Energies in QM/MM Free Energy Simulations

The use of the most accurate (i.e., QM or QM/MM) levels of theory for free energy simulations (FES) is typically not possible. Primarily, this is because the computational cost associated with the extensive configurational sampling needed for converging FES is prohibitive. To ensure the feasibility of QM-based FES, the “indirect” approach is generally taken, necessitating a free energy calculation between the MM and QM/MM potential energy surfaces. Ideally, this step is performed with standard free energy perturbation (Zwanzig’s equation) as it only requires simulations be carried out at the low level of theory; however, work from several groups over the past few years has conclusively shown that Zwanzig’s equation is ill-suited to this task. As such, many approximations have arisen to mitigate difficulties with Zwanzig’s equation. One particularly popular notion is that the convergence of Zwanzig’s equation can be improved by using interaction energy differences instead of total energy differences. Although problematic numerical fluctuations (a major problem when using Zwanzig’s equation) are indeed reduced, our results and analysis demonstrate that this “interaction energy approximation” (IEA) is theoretically incorrect, and the implicit approximation invoked is spurious at best. Herein, we demonstrate this via solvation free energy calculations using IEA from two different low levels of theory to the same target high level. Results from this proof-of-concept consistently yield the wrong results, deviating by ∼1.5 kcal/mol from the rigorously obtained value