Molecular fragment dynamics (MFD) is a variant of dissipative particle dynamics (DPD), a coarse-grained mesoscopic simulation technique for isothermal complex fuids and soft matter systems with particles that are chosen to be adequate fluid elements. MFD choses its particles to be small molecules which may be connected by harmonic springs to represent larger molecular entities in order to maintain a comparatively accurate representation of covalent bonding and molecular characteristics. For this study the MFD approach is extended to accomplish long-term simulations (up to the microsecond scale) of large molecular ensembles (representing millions of atoms) containing phospholipid membranes, peptides, and proteins. For peptides and proteins a generally applicable fragmentation scheme is introduced in combination with specific backbone forces that keep native spatial shapes with adequate levels of flexibility or rigidity. The new approach is demonstrated by MFD simulations of the formation and characteristics of phospholipid membranes and vesicles, vesicle-membrane fusion, the backbone force dependency of the overall structural flexibility of dumbbell-shaped Calmodulin, the stability of subunit-aggregation of tetrameric hemoglobin, and the collaborative interaction of Kalata B1 cyclotides with a phospholipid membrane. All findings are in reasonable agreement with experimental as well as alternative simulation results. Thus, the extended MFD approach may become a new tool for biomolecular system studies to allow for comparatively fast simulative investigations in combination with a comparatively high chemical granularity.

Cyclotide-induced membrane disruption is studied at the microsecond timescale by Dissipative Particle Dynamics (DPD) to quantitatively estimate a kinetic rate constant for membrane lipid extraction with a "sandwich" interaction model where two bilayer membranes enclose a cyclotide/water compartment. The obtained bioactivity trends for cyclotides Kalata B1, Cycloviolacin O2 and selected mutants with different membrane types are in agreement with experimental findings: For all membranes investigated, Cycloviolacin O2 shows a higher lipid extraction activity than Kalata B1. The presence of cholesterol leads to a decreased cyclotide activity compared to cholesterol-free membranes. Phosphoethanolamine-rich membranes exhibit an increased membrane disruption. A cyclotide's "hydrophobic patch" surface area is important for its bioactivity.A replacement of or with charged amino acid residues may lead to super-mutants with above-native activity but without simple charge-activity patterns. Cyclotide mixtures show linearly additive bioactivities without significant sub-or over-additive effects. The proposed method can be applied as a fast and easy-to-use tool for exploring structureactivity relationships of cyclotides/membrane systems: With the open software provided, the rate constant of a single cyclotide/membrane system can be determined in about one day by a scientific end-user without programming skills.

Jdpd is an open Java simulation kernel for Molecular Fragment Dissipative Particle Dynamics with parallelizable force calculation, efficient caching options and fast property calculations. It is characterized by an interface and factory-pattern driven design for simple code changes and may help to avoid problems of polyglot programming. Detailed input/output communication, parallelization and process control as well as internal logging capabilities for debugging purposes are supported. The new kernel may be utilized in different simulation environments ranging from flexible scripting solutions up to fully integrated “all-in-one” simulation systems.

MFsim is an open Java all-in-one rich-client computing environment for mesoscopic simulation with Jdpd as its default simulation kernel for Molecular Fragment (Dissipative Particle) Dynamics. The new environment comprises the complete preparation-simulation–evaluation triad of a mesoscopic simulation task and especially enables biomolecular simulation tasks with peptides and proteins. Productive highlights are a SPICES molecular structure editor, a PDB-to-SPICES parser for particle-based peptide/protein representations, a support of polymer definitions, a compartment editor for complex simulation box start configurations, interactive and flexible simulation box views including analytics, simulation movie generation or animated diagrams. As an open project, MFsim allows for customized extensions for different fields of research.

Simplified Particle Input ConnEction Specification (SPICES) is a particle-based molecular structure representation derived from straightforward simplifications of the atom-based SMILES line notation. It aims at supporting tedious and error-prone molecular structure definitions for particle-based mesoscopic simulation techniques like Dissipative Particle Dynamics by allowing for an interplay of different molecular encoding levels that range from topological line notations and corresponding particle-graph visualizations to 3D structures with support of their spatial mapping into a simulation box. An open Java library for SPICES structure handling and mesoscopic simulation support in combination with an open Java Graphical User Interface viewer application for visual topological inspection of SPICES definitions are provided.