Justin Gullingsrud's research while affiliated with D. E. Shaw Research and other places
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Publications (19)
The design of numerical integrators for particle simulations with arbitrary potentials entails fundamental trade-offs between the accuracy achieved and the amount of computation required. Here we introduce a class of explicit variational integrators designed to achieve high accuracy for quadratic potentials, with little additional computation relat...
Events of scientific interest in molecular dynamics (MD) simulations, including conformational changes, folding transitions, and translocations of ligands and reaction products, often correspond to high-level structural rearrangements that alter contacts between molecules or among different parts of a molecule. Due to advances in computer architect...
Events of scientific interest in molecular dynamics (MD) simulations, including conformational changes, folding transitions, and translocations of ligands and reaction products, often correspond to high-level structural rearrangements that alter contacts between molecules or among different parts of a molecule. Due to advances in computer architect...
As parallel algorithms and architectures drive the longest molecular dynamics (MD) simulations towards the millisecond scale, traditional sequential post-simulation data analysis methods are becoming increasingly untenable. Inspired by the programming interface of Google's MapReduce, we have built a new parallel analysis framework called HiMach, wh...
Peptide insertion, positioning, and stabilization in a model membrane are probed via an all-atom molecular dynamics (MD) simulation. One peptide (WL5) is simulated in each leaflet of a solvated dimyristoylglycero-3-phosphate (DMPC) membrane. Within the first 5 ns, the peptides spontaneously insert into the membrane and then stabilize during the rem...
SR protein kinase 1 (SRPK1) is a constitutively active kinase, which processively phosphorylates multiple serines within its substrates, ASF/SF2. We describe crystallographic, molecular dynamics, and biochemical results that shed light on how SRPK1 preserves its constitutive active conformation. Our structure reveals that unlike other known active...
Mechanosensitivity is a ubiquitous sensory mechanism found in living organisms. The simplest known mechanotransducing mechanism is found in bacteria in the form of the mechanosensitive membrane channel of large conductance, MscL. This channel has been studied extensively using a variety of methods at a functional and structural level. The channel i...
The distribution of surface tension within a lipid bilayer, also referred to as the lateral pressure profile, has been the subject of theoretical scrutiny recently due to its potential to radically alter the function of biomedically important membrane proteins. Experimental measurements of the pressure profile are still hard to come by, leaving fir...
The nicotinic acetylcholine receptor is a prototype ligand-gated ion channel that mediates signal transduction in the neuromuscular junctions and other cholinergic synapses. The molecular basis for the energetics of ligand binding and unbinding is critical to our understanding of the pharmacology of this class of receptors. Here, we used steered mo...
Recent crystal structures have revealed that regulatory subunit RIalpha of PKA undergoes a dramatic conformational change upon complex formation with the catalytic subunit. Molecular dynamics studies were initiated to elucidate the contributions of intrinsic conformational flexibility and interactions with the catalytic subunit in formation and sta...
The function of membrane proteins often depends on the proteins' interaction with their lipid environment, spectacularly so in the case of mechanosensitive channels, which are gated through tension mediated by the surrounding lipids. Lipid bilayer tension is distributed quite inhomogeneously, but neither the scale at which relevant variation takes...
Steered molecular dynamics simulations of the mechanosensitive channel of large conductance, MscL, were used to investigate how forces arising from membrane tension induce gating of the channel. A homology model of the closed form of MscL from Escherichia coli was subjected to external forces of 35-70 pN applied to residues near the membrane-water...
The mechanosensitive channel of large conductance (MscL) in prokaryotes plays a crucial role in exocytosis as well as in the response to osmotic downshock. The channel can be gated by tension in the membrane bilayer. The determination of functionally important residues in MscL, patch-clamp studies of pressure-conductance relationships, and the rece...
Molecular recognition and mechanical properties of proteins govern molecular processes in the cell that can cause disease and can be targeted for drug design. Single molecule measurement techniques have greatly advanced knowledge but cannot resolve enough detail to be interpreted in terms of protein structure. We seek to complement the observations...
Atomic force microscopy (AFM) experiments and steered molecular dynamics (SMD) simulations have revealed much about the dynamics of protein-ligand binding and unbinding, as well as the stretching and unfolding of proteins. Both techniques induce ligand unbinding or protein unfolding by applying external mechanical forces to the ligand or stretched...
Citations
... Even with the most advanced resources available, simulating these processes can still take months or even years. 3 A variety of methods, generally called enhanced sampling techniques, have emerged as a solution to the rare event problem. For a comprehensive review of the enhanced sampling methods used in molecular dynamics simulations, interested readers can refer to Refs. ...
... An accurate and detailed description of the binding/unbinding processes requires explicit representation of water molecules, which is possible only in MD simulations. Unfortunately predicting the binding configuration for a protein-ligand complex from MD simulations is a very slow process, so it can be reliably applied to those few cases where the complex structure has already been determined from experiments (9)(10)(11)(12)(13)(14)(15)(16)(17). For the majority of cases lacking a complex structure, one can use a docking method to generate initial binding positions, which are subsequently refined in MD simulations (18)(19)(20)(21)(22). ...
... HDF5/DMS [31] uses the HDF5 and PnetCDF I/O library calls to expose a virtual file to staging nodes. GLEAN [141,144] is another example of a simulation/visualization coupling tool initiated by making HDF5 and PnetCDF I/O library calls. DataSpaces [48] stores the simulation data on staging nodes with a spatially coherent layout and acts as a server for client applications. ...
... The study conducted MD simulations on the SLMAPK1 + Albaflavenone dock complex utilizing Desmond 2020.1 software, as described by Shaw et al. [37]. The system was set up utilizing the OPLS-2005 force field [5,8,39] and the SPC explicit solvent model for water molecules [22]. The dimensions of the solvent box were specified as 10 × 10 × 10 Å. ...
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... Production simulations were performed in the NPT ensemble at 310 K using the Martyna-Tobias-Klein barostat (36) and the Nosé-Hoover thermostat (37). The simulation time step was 2.5 fs, using a modified r-RESPA integrator (38) and evaluating long-range electrostatics every three time steps. Bond lengths to hydrogen atoms were constrained using an implementation (39) of M-SHAKE (40), and electrostatic forces were calculated using the u-series method. ...
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... The pressure is uniform in the aqueous environment and the normal pressure, P N , also across the bilayer. However, the lateral pressure, P L , has a characteristic profile that averages out to the value of the normal pressure [53][54][55][56][57][58][59][60][61][62]. For the purpose of this study, we only consider quasistatic processes of a restricted type in which both T , and P N remain constant and uniform. ...
... An alternative coarse-graining method yields a network weighted by local energy diffusion coefficients calculated in terms of normal modes [19]. The weights for the network are expressed in terms of the matrix elements of the energy current operator, S, which in harmonic approximation can be written in terms of the Hessian matrix, H, and eigenmodes, e, of the object [90]. The mode diffusivity, in turn, can be expressed in terms of the matrix elements of S [90]. ...
Reference: Topology Results on of Oligomeric Proteins
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... Our new design paradigm for enhancing mechanical stability is based on a statistical analysis of residues important for the global unfolding process, as well as on an analysis of the biophysical and biochemical properties of SMD trajectories, which is different from the cross-linking strategy originally applied by Sharma et al. (2007). The present work is an extension of previously proposed strategies (Wriggers et al., 2009;Shaw et al., 2010;Kovacs and Wriggers, 2016;Kovacs et al., 2017) aimed at detecting functionally relevant mechanisms in proteins. The new approach efficiently matches fast local movements (secondary or tertiary structure rearrangements) with slow global protein behavior (characterized by an activity function or order parameter). ...
... In this process, the backbone atoms of DNA were taken as the fixed atoms and alpha carbons in AGT were taken as the dummy atoms; and were pulled from their center of mass (COM) along the positive x-direction with constant velocity (v = dx∕dt) in water and ions environment so that the SMD atom experiences the force F(t) = k(v t − Δx) [34], providing the external potential energy [35], where k (= 5 kcal mol −1 Å −2 ) is the spring constant and gives the stiffness of the applied harmonic restraining force, and Δx (t) = x (t) − x 0 , is the displacement between the molecules being actual position x (t) and initial position x 0 and n is the unit vector along the direction of pulling. ...
... We employed a combination of custom scripting and established software packages to analyze the data. Custom Tcl scripts were written to automate the extraction of features within VMD software [72], [73], [74]. The extracted data was analyzed with pandas [75], [76] and NumPy [77], and graphics were generated using Matplotlib [78]. ...
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