A5039906501- Protein Structure and Dynamics
- Distributed and Parallel Computing Systems
- Protein Degradation and Inhibitors
- Scientific Computing and Data Management
- Spectroscopy and Quantum Chemical Studies
- Advanced Data Storage Technologies
- Parallel Computing and Optimization Techniques
- Bioinformatics and Genomic Networks
- Ubiquitin and proteasome pathways
- Microbial Metabolic Engineering and Bioproduction
- Numerical methods for differential equations
- Gene Regulatory Network Analysis
- Mass Spectrometry Techniques and Applications
- Enzyme Structure and Function
- Peptidase Inhibition and Analysis
- Model Reduction and Neural Networks
- Slime Mold and Myxomycetes Research
- Nonlinear Dynamics and Pattern Formation
- Mathematical Biology Tumor Growth
- ATP Synthase and ATPases Research
- Cellular Mechanics and Interactions
- Protein Tyrosine Phosphatases
- Quantum, superfluid, helium dynamics
- Scientific Research and Discoveries
- RNA and protein synthesis mechanisms
APA Corporation (United States)
2024-2025
D. E. Shaw Research
2019-2023
Roivant Sciences (United States)
2021-2023
University of Notre Dame
2007-2016
Stanford University
2009
Northwestern University
2009
Notre Dame University
2007
University of Illinois Urbana-Champaign
1999
In this paper we show the possibility of using very mild stochastic damping to stabilize long time step integrators for Newtonian molecular dynamics. More specifically, stable and accurate integrations are obtained coefficients that only a few percent natural decay rate processes interest, such as velocity autocorrelation function. Two new multiple stepping integrators, Langevin Molly (LM) Brünger–Brooks–Karplus–Molly (BBK–M), introduced in paper. Both use mollified impulse method term. LM...
Abstract Motivation: CompuCell is a multi-model software framework for simulation of the development multicellular organisms known as morphogenesis. It models interaction gene regulatory network with generic cellular mechanisms, such cell adhesion, division, haptotaxis and chemotaxis. A combination state automaton stochastic local rules set differential equations, including subcellular ordinary equations extracellular reaction–diffusion partial model regulation. This in turn controls...
Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated diseases. A key step this process the formation of ternary complex where heterobifunctional molecule induces proximity an E3 ligase to interest (POI), thus facilitating ubiquitin transfer POI. In work, we characterize 3 steps TPD process. (1) We simulate SMARCA2 bromodomain and VHL by combining hydrogen-deuterium exchange mass spectrometry with weighted ensemble molecular dynamics...
GlueMap is a computational toolkit to discover and optimize molecular glues. The tool integrates structural pharmacodynamic modeling, dynamics (MD), machine learning model targeted protein degradation (TPD) mediated by glues (MGs). effectively models ternary complexes, predicts their thermodynamic stabilities, evaluates downstream effects like ubiquitination efficiency. We validated GlueMap's capabilities through two case studies: CRBN-dependent of GSPT1 DDB1-dependent CDK12. For CRBN-GSPT1,...
Simulations of the dynamics biomolecules have been greatly accelerated by use multiple time-stepping methods, such as Verlet-I/r-RESPA (reversible reference system propagator algorithms) method, which is based on approximating “slow” forces widely separated impulses. Indeed, numerical experiments shown that time steps 4 fs are possible for these slow but unfortunately also a long step 5 results in dramatic energy drift. To overcome this instability, symplectic modification impulsive method...
The best simple method for Newtonian molecular dynamics is indisputably the leapfrog Stormer-Verlet method. appropriate generalization to Langevin unclear. An analysis presented comparing an 'impulse method' (kick; fluctuate; kick), 1982 of van Gunsteren and Berendsen, Brünger-Brooks-Karplus (BBK) It shown how impulse Gunsteren-Berendsen methods can be implemented as efficiently BBK Other considerations suggest that basic dynamics, with a close contender.
In this paper we present the foundation of a unified, object-oriented, three-dimensional biomodelling environment, which allows us to integrate multiple submodels at scales from subcellular those tissues and organs. Our current implementation combines modified discrete model statistical mechanics, Cellular Potts Model, with continuum reaction–diffusion state automaton well-defined conditions for cell differentiation transitions genetic regulation. This environment rapidly compactly create...
We present COMPUCELL3D, a software framework for three-dimensional simulation of morphogenesis in different organisms. COMPUCELL3D employs biologically relevant models cell clustering, growth, and interaction with chemical fields. uses design patterns speed, efficient memory management, extensibility, flexibility to allow an almost unlimited variety simulations. have verified by building model growth skeletal pattern formation the avian (chicken) limb bud. Binaries source code are available,...
This paper shows that in molecular dynamics (MD) when constant- energy (NVE) simulations of Newton's equations motion are attempted using the multiple time stepping (MTS) integrator Verlet-I/r-RESPA/Impulse, there nonlinear instabilities longest step size is a third or possibly fourth period(s) fastest motion(s) system. demonstrated both through thorough set computer experiments and analysis model problem. The numerical include not only unconstrained simulation droplet flexible water...
Protein-protein interactions are often mediated by flexible loops that experience conformational dynamics on the microsecond to millisecond time scales. NMR relaxation studies can map these dynamics. However, defining network of inter-converting conformers underlie data remains generally challenging. Here, we combine experiments with simulation visualize networks conformers. We demonstrate our approach apo Pin1-WW domain, for which has revealed a loop in range. sample and cluster free energy...
Chemically induced proximity between certain endogenous enzymes and a protein of interest (POI) inside cells may cause post-translational modifications to the POI with biological consequences potential therapeutic effects. Heterobifunctional (HBF) molecules that bind one functional part target other an E3 ligase induce formation target-HBF-E3 ternary complex, which can lead ubiquitination proteasomal degradation POI. Targeted (TPD) by HBFs offers promising approach modulate...
ProtoMol is a high-performance framework in C++ for rapid prototyping of novel algorithms molecular dynamics and related applications. Its flexibility achieved primarily through the use inheritance design patterns (object-oriented programming). Performance obtained by using templates that enable generation efficient code sections critical to performance (generic The encapsulates important optimizations can be used developers, such as parallelism force computation. based on domain analysis...
One goal of contemporary proteome research is the elucidation cellular protein interactions. Based on currently available protein-protein interaction and domain data, we introduce a novel method, maximum specificity set cover (MSSC), for prediction In our approach, map relationship between interactions proteins their corresponding architectures to generalized weighted problem. The application greedy algorithm provides sets which explain presence largest degree specificity. Utilizing data S....
We propose a novel normal mode multiple time stepping Langevin dynamics integrator called NML. The aim is to approximate the kinetics or thermodynamics of biomolecule by reduced model based on decomposition dynamical space. Our basis set uses eigenvectors mass reweighted Hessian matrix calculated with biomolecular force field. This particular choice has advantage an ordering according eigenvalues, which have physical meaning being square frequency. Low frequency eigenvalues correspond more...
To gain performance, developers often build scientific applications in procedural languages, such as C or Fortran, which unfortunately reduces flexibility. address this imbalance, the authors present CompuCell3D, a multitiered, flexible, and scalable problem-solving environment for morphogenesis simulations that's written C++ using object-oriented design patterns.
Proteins and other macromolecules have coupled dynamics over multiple time scales (from femtosecond to millisecond beyond) that make resolving molecular challenging. We present an approach based on periodically decomposing the of a macromolecule into slow fast modes scalable coarse-grained normal mode analysis. A Langevin equation is used propagate slowest degrees freedom while minimizing nearly instantaneous freedom. numerical results showing steps up 1000 fs can be used, with real speedups...
Hybrid Monte Carlo (HMC) is a rigorous sampling method that uses molecular dynamics (MD) as global move. The acceptance rate of HMC decays exponentially with system size. shadow hybrid (SHMC) was previously introduced to reduce this performance degradation by instead from the Hamiltonian defined for MD when using symplectic integrator. SHMC’s limited need generate momenta step nonseparable Hamiltonian. We introduce separable (S2HMC) based on formulation leapfrog/Verlet integrator corresponds...
Over the past decade, high performance applications have embraced parallel programming and computing models. While offers advantages such as good utilization of dedicated hardware resources, it also has several drawbacks poor fault-tolerance, scalability, ability to harness available resources during run-time. The advent cloud presents a viable promising alternative because its in offering distributed model. In this work, we establish directives that serve guidelines for design...
Octopamine receptors (OARs) perform key functions in the biological pathways of primarily invertebrates, making this class G-protein coupled (GPCRs) a potentially good target for insecticides. However, lack structural and experimental data insect-essential GPCR family has promoted development homology models that are representations their equivalents silico screening small molecules. Two Anopheles gambiae OARs were cloned, analysed functionally characterized using heterologous cell reporter...
A limitation of traditional molecular dynamics (MD) is that reaction rates are difficult to compute. This due the rarity observing transitions between metastable states since high energy barriers trap system in these states. Recently weighted ensemble (WE) family methods have emerged which can flexibly and efficiently sample conformational space without being trapped allow calculation unbiased rates. However, while WE correctly efficiently, a scalable implementation applicable interesting...
Targeted protein degradation (TPD) is emerging as a promising therapeutic approach for cancer and other diseases, with an increasing number of programs demonstrating its efficacy in human clinical trials. One notable method TPD Proteolysis Targeting Chimeras (PROTACs, or heterobifunctional degraders) that selectively degrade interest (POI) through E3-ligase induced ubiquitination followed by proteasomal degradation. PROTACs utilize warhead-linker-ligand architecture to bring the POI (bound...
The authors accelerate the replica exchange method through an efficient all-pairs exchange. A proof of detailed balance is shown along with analytical estimate enhanced efficiency. new provides asymptotically four fold speedup conformation traversal for counts 8 and larger typical rates. Experimental tests using blocked alanine dipeptide demonstrate method’s correctness show approximate sampling efficiency improvement 100% according to potential energy cumulative averages ergodic measure. An...