MiMiC: A high-performance framework for multiscale molecular dynamics simulations.

MiMiC is a framework for performing multiscale simulations in which loosely coupled external programs describe individual subsystems at different resolutions and levels of theory. To make it highly efficient and flexible, we adopt an interoperable approach based on a multiple-program multiple-data (MPMD) paradigm, serving as an intermediary responsible for fast data exchange and interactions between the subsystems. The main goal of MiMiC is to avoid interfering with the underlying parallelization of the external programs, including the operability on hybrid architectures (e.g., CPU/GPU), and keep their setup and execution as close as possible to the original. At the moment, MiMiC offers an efficient implementation of electrostatic embedding quantum mechanics/molecular mechanics (QM/MM) that has demonstrated unprecedented parallel scaling in simulations of large biomolecules using CPMD and GROMACS as QM and MM engines, respectively. However, as it is designed for high flexibility with general multiscale models in mind, it can be straightforwardly extended beyond QM/MM. In this article, we illustrate the software design and the features of the framework, which make it a compelling choice for multiscale simulations in the upcoming era of exascale high-performance computing.

A multiple time step algorithm for trajectory surface hopping simulations.

A multiple time step (MTS) algorithm for trajectory surface hopping molecular dynamics has been developed, implemented, and tested. The MTS scheme is an extension of the ab initio implementation for Born-Oppenheimer molecular dynamics presented in the work of Liberatore et al. [J. Chem. Theory Comput. 14, 2834 (2018)]. In particular, the MTS algorithm has been modified to enable the simulation of non-adiabatic processes with the trajectory surface hopping (TSH) method and Tully's fewest switches algorithm. The specificities of the implementation lie in the combination of Landau-Zener and Tully's transition probabilities during the inner MTS time steps. The new MTS-TSH method is applied successfully to the photorelaxation of protonated formaldimine, showing that the important characteristics of the process are recovered by the MTS algorithm. A computational speed-up between 1.5 and 3 has been obtained compared to standard TSH simulations, which is close to the ideal values that could be obtained with the computational settings considered.

Recent Advances in First-Principles Based Molecular Dynamics.

First-principles molecular dynamics (FPMD) and its quantum mechanical-molecular mechanical (QM/MM) extensions are powerful tools to follow the real-time dynamics of a broad variety of systems in their ground as well as electronically excited states. The continued advances in computational power have enabled simulations of QM regions of larger sizes for more extended time scales. In addition, development of the parallel algorithms has boosted the performance of QM/MM methods even on existing computer architectures. In the case of density functional-based FPMD, systems of several hundreds to thousands of atoms can now be customarily simulated for tens to hundreds of picoseconds. In spite of this progress, the time scale limitations remain severe, especially when high-rung exchange-correlation functionals or high-level wave function based quantum mechanical methods are used. To ameliorate this, a large number of enhanced sampling methods have been introduced but most of the approaches that have been developed to increase the efficiency of FPMD based simulations sacrifice the real-time dynamics in favor of enhancing sampling. Here, we present some recent advances in boosting the efficiency of FPMD based simulations while keeping the full dynamic information. These include a highly efficient recent implementation of FPMD-based QM/MM simulations that not only enables fully flexible combinations of different electronic structure methods and force fields via a highly efficient communication library, it also fully exploits parallelism for both quantum and classical descriptions. The second type of acceleration methods we discuss is a large family of specially devised multiple-time-step algorithms that make use of suitable breakups of the total nuclear forces into fast components that can be calculated via lower level methods and slowly varying correction forces evaluated with a high-level method at long time intervals. The computational gain of this scheme mostly depends on the cost difference between the two methods and advantageous combinations can yield large speedups without compromising the accuracy of the high-level method. And finally, the third class of FPMD acceleration methods presented here are machine learning models to accelerated FPMD and their powerful combinations with multiple-time-step techniques. The combination of all the approaches enables substantial speedups of FPMD simulations of several orders of magnitude while fully preserving the real-time dynamics and accuracy.

Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as New Drug Candidates for Schistosomiasis*.

Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its strengths and weaknesses, is the only treatment available. We previously reported findings on three lead compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene-containing (Fc-CH2 -OXA), ruthenocene-containing (Rc-CH2 -OXA) and benzene-containing (Ph-CH2 -OXA) OXA derivatives. These derivatives showed excellent in vitro activity against both Schistosoma mansoni larvae and adult worms and S. haematobium adult worms, and were also active in vivo against adult S. mansoni. Encouraged by these promising results, we conducted additional in-depth preclinical studies and report in this investigation on metabolic stability studies, in vivo studies on S. haematobium and juvenile S. mansoni, computational simulations, and formulation development. Molecular dynamics simulations supported the in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reason why the promising in vitro activity did not translate into in vivo activity on S. haematobium. This limitation could not be overcome by the formulation of lipid nanocapsules as a way to improve the in vivo activity. Further studies should focus on increasing the compound's bioavailability, to reach an active concentration in the microenvironment of the parasite.

Ephemeral Protein Binding to DNA Shapes Stable Nuclear Bodies and Chromatin Domains.

Fluorescence microscopy reveals that the contents of many (membrane-free) nuclear bodies exchange rapidly with the soluble pool while the underlying structure persists; such observations await a satisfactory biophysical explanation. To shed light on this, we perform large-scale Brownian dynamics simulations of a chromatin fiber interacting with an ensemble of (multivalent) DNA-binding proteins able to switch between an "on" (binding) and an "off" (nonbinding) state. This system provides a model for any DNA-binding protein that can be posttranslationally modified to change its affinity for DNA (e.g., through phosphorylation). Protein switching is a nonequilibrium process, and it leads to the formation of clusters of self-limiting size, where individual proteins in a cluster exchange with the soluble pool with kinetics similar to those seen in photobleaching experiments. This behavior contrasts sharply with that exhibited by nonswitching proteins, which are permanently in the on-state; when these bind to DNA nonspecifically, they form clusters that grow indefinitely in size. To explain these findings, we propose a mean-field theory from which we obtain a scaling relation between the typical cluster size and the protein switching rate. Protein switching also reshapes intrachromatin contacts to give networks resembling those seen in topologically associating domains, as switching markedly favors local (short-range) contacts over distant ones. Our results point to posttranslational modification of chromatin-bridging proteins as a generic mechanism driving the self-assembly of highly dynamic, nonequilibrium, protein clusters with the properties of nuclear bodies.