Rigid Body Brownian Dynamics

by Christopher C. Roberts

GeomBD2 is a rigid body Brownian dynamics software for determining interenzyme intermediate transfer rates and substrate association rates in biomolecular complexes. Substrate and intermediate association rates for a series of enzymes or biomolecules can be compared between the freely diffusing disorganized configuration and various colocalized or complexed arrangements for kinetic investigation of enhanced intermediate transfer. In addition, enzyme engineering techniques, such as synthetic protein conjugation, can be computationally modeled and analyzed to better understand changes in substrate association relative to native enzymes. Tools are provided to determine non-specific ligand-receptor association residence times, and to visualize common sites of non-specific association of substrates on receptor surfaces.

[1] Roberts, C. C. and Chang, C-E. A.*, Modeling of Enhanced Catalysis in Multi-enzyme Nanostructures: Effect of Molecular Scaffolds, Spatial Organization, and Concentration. J. of Chemical Theory and Computation, 2015 [link]

[2] Roberts, C. C. and Chang, C-E. A.*, Analysis of Ligand-Receptor Association and Intermediate Transfer Rates in Multi-enzyme Nanostructures with All-Atom Brownian Dynamics Simulations. J. of Physical Chemistry B. 2016 [link]


Energy Barrier Guided Drug Design

by Hari Datt Pandey

eBGDD is a software package that performs necessary steps of energy barrier guided drug design. Binding kinetics (BK) can play a central role in drug discovery because BK parameters predict the pharmacological response. Every step of the drug discovery pipeline emphasizes the drug-receptor BK. The dissociative half-life or drug-target residence time is an essential indicator in lead optimization. A free energy profile is crucial for calculating the reaction rate and recognizing the reaction mechanism; thus, a reasonable estimate of the free energy profile is essential for obtaining the BK profile. Calculating the potential of mean force (PMF) as a free energy profile using atomistic simulations is a promising approach to investigating binding kinetics. Drug binding kinetics is studied primarily by second-order association rate constant (kon) and first-order dissociation rate constant (koff). Drug-target binding and unbinding interactions produce the pharmacological response; therefore, optimization of drug molecules can be improved if all the binding energy barriers and drug-receptor interactions are known. The intermediate energy barriers between the bound and unbound states are significant for drug design. This eBGDD software implements a hybrid method of milestoning with enhanced sampling to compute all the energy barriers between bound and unbound state. The phase space is uniquely represented using essential dynamics. Vital dynamics are obtained using principal components (PCs) of internal motions. A 2-D phase space representation is constructed using projections of the first two principal components on the trajectory frames, and milestones are built on the projection space. After making milestones, we chose a reasonable number of conformations from each milestone and performe short classical unbiased MD simulation. The eBGDD package computes PMF, residence time, and transition time between one milestone and another. Most importantly, it calculates significant intermediate energy barriers. We can also compute kon and koff using the package. It is a software written in multi-CPU parallelization-enabled C++ language. The program can apply any number of CPUs so that one can handle any trajectory size. The eBGDD code is designed in a LINUX environment, and makes use of LINUX tools and bash scripts for setting up MD simulations. After sampling the dissociation path, stripping solvent and ions from the trajectory is highly recommended to reduce the computational cost. eBGDD itself does not perform cMD or any enhanced sampling simulations and instead uses AMBER, GROMACS, or other similar software for such tasks.


by Rizi Ai

T-Analyst is a user-friendly computer program for analyzing protein dynamics and conformational changes from MD simulations in internal bond-angle-torsion coordinates. The program is provided with tutorial and full source code in Perl.

[1] Ai, R., Fatmi, Q. and Chang, C-E. A., T-Analyst: a program for efficient analysis of protein conformational changes by torsion angles. J. of Computer-Aided Molecular Design. 2010 [link]