We describe MUSCLE, a new computer program for creating multiple alignments of protein sequences. Elements of the algorithm include fast distance estimation using kmer counting, progressive alignment using a new profile function we call the logexpectation score, and refinement using treedependent restricted partitioning. The speed and accuracy of MUSCLE are compared with T-Coffee, MAFFT and CLUSTALW on four test sets of reference alignments: BAliBASE, SABmark, SMART and a new benchmark, PREFAB. MUSCLE achieves the highest, or joint highest, rank in accuracy on each of these sets. Without refinement, MUSCLE achieves average accuracy statistically indistinguishable from T-Coffee and MAFFT, and is the fastest of the tested methods for large numbers of sequences, aligning 5000 sequences of average length 350 in 7 min on a current desktop computer. The MUSCLE program, source code and PREFAB test data are freely available at http://www.drive5. com/muscle.

MUSCLE: multiple sequence alignment with high accuracy and high throughput

CHARMM (Chemistry at HARvard Macromolecular Mechanics) is a highly flexible computer program which uses empirical energy functions to model macromolecular systems. The program can read or model build structures, energy minimize them by first- or second-derivative techniques, perform a normal mode or molecular dynamics simulation, and analyze the structural, equilibrium, and dynamic properties determined in these calculations. The operations that CHARMM can perform are described, and some implementation details are given. A set of parameters for the empirical energy function and a sample run are included.

CHARMM: A program for macromolecular energy, minimization, and dynamics calculations

For a successful analysis of the relation between amino acid sequence and protein structure, an unambiguous and physically meaningful definition of secondary structure is essential. We have developed a set of simple and physically motivated criteria for secondary structure, programmed as a pattern-recognition process of hydrogen-bonded and geometrical features extracted from x-ray coordinates. Cooperative secondary structure is recognized as repeats of the elementary hydrogen-bonding patterns “turn” and “bridge.” Repeating turns are “helices,” repeating bridges are “ladders,” connected ladders are “sheets.” Geometric structure is defined in terms of the concepts torsion and curvature of differential geometry. Local chain “chirality” is the torsional handedness of four consecutive Cα positions and is positive for right-handed helices and negative for ideal twisted β-sheets. Curved pieces are defined as “bends.” Solvent “exposure” is given as the number of water molecules in possible contact with a residue. The end result is a compilation of the primary structure, including SS bonds, secondary structure, and solvent exposure of 62 different globular proteins. The presentation is in linear form: strip graphs for an overall view and strip tables for the details of each of 10.925 residues. The dictionary is also available in computer-readable form for protein structure prediction work.

Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features

6.2.2. Definition of Effective Properties 3064 6.3. Response Properties to Magnetic Fields 3066 6.3.1. Nuclear Shielding 3066 6.3.2. Indirect Spin−Spin Coupling 3067 6.3.3. EPR Parameters 3068 6.4. Properties of Chiral Systems 3069 6.4.1. Electronic Circular Dichroism (ECD) 3069 6.4.2. Optical Rotation (OR) 3069 6.4.3. VCD and VROA 3070 7. Continuum and Discrete Models 3071 7.1. Continuum Methods within MD and MC Simulations 3072

/pdf/quantum-mechanical-continuum-solvation-models-3edv963g14.pdf

Quantum mechanical continuum solvation models.

This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.

/pdf/gromacs-fast-flexible-and-free-15aazpel5u.pdf

GROMACS: Fast, flexible, and free

Cerebral aneurysms are a serious clinical challenge, with ~half resulting in death or disability. Treatment via endovascular coiling significantly reduces the chances of rupture, but the technique has failure rates between 25-40%. This presents a pressing need to develop a method for determining optimal coil deployment strategies. Quantification of aneurysm hemodynamics through computational fluid dynamics (CFD) has the potential to significantly improve the understanding of the mechanics of aneurysm coiling and improve treatment outcomes, but accurately representing the coil mass in CFD simulations remains a challenge. We have used the Finite Element Method (FEM) for simulating patient-specific coil deployment based on mechanical properties and coil geometries provided by the device manufacturer for n=4 ICA aneurysms for which 3D printed in vitro models were also generated, coiled, and scanned using ultra-high resolution synchrotron micro-CT. The physical and virtual coil geometries were voxelized onto a binary structured grid and porosity maps were generated for geometric comparison. The average binary accuracy score is 0.836 and the average error in porosity map is 6.3%. We then conduct patient-specific CFD simulations of the aneurysm hemodynamics using virtual coils geometries, micro-CT generated oil geometries, and using the porous medium method to represent the coil mass. Hemodynamic parameters of interest including were calculated for each of the CFD simulations. The average error across hemodynamic parameters of interest is ~19%, a 58% reduction from the average error of the porous media simulations, demonstrating a marked improvement in the accuracy of CFD simulations using FEM generated coil geometries.

https://www.medrxiv.org/content/medrxiv/early/2023/03/01/2023.02.27.23286512.full.pdf

Improving Computational Fluid Dynamics Simulations of Coiled Aneurysms Using Finite Element Modeling


 Background:
 While mechanical thrombectomy (MT) has become the standard of care for acute stroke patients presenting with large vessel occlusion (LVO) and salvageable brain tissue, limited data is currently available regarding the benefits of MT in patents with medium vessel occlusions (MeVO) especially in the posterior circulation (P2 occlusions).
 
 
 Methods:
 We used the Stroke Thrombectomy and Aneurysm registry (STAR) which included data from 35 stroke centers in North America, Europe, Asia, and South America. We included patients who presented with MeVO in the M2, M3 or P2 segments and underwent MT. We used a Generalized Linear Model to assess the relationship between location of occlusion and outcomes.
 
 
 Results:
 9812 patients were included in STAR at the time of this analysis; 43 underwent MT for P2 occlusion, 130 underwent MT for M3 occlusion; and 1273 underwent MT for M2 occlusion. There was no difference in age, sex, race, rate of IV-tPA and stroke severity between patients in all 3 groups (Table 1). There was a trend toward lower rate of atrial fibrillation in patients with P2 and M3 occlusions. Patients with P2 occlusions were less likely to achieve successful recanalization (modified treatment in cerebral infarction score≥2b); intraarterial thrombolysis was used less in P2 occlusions (4.7% compared to 16.2% in M3 occlusions and 10.1% in M2 occlusions). However, there was no difference in the rate of successful first pass. On multivariable analysis, P2 occlusions were not associated with hemorrhagic transformation (OR 2.0, 95% CI 0.7-5.7, P 0.186), 90-day mortality (OR 0.5, 95% CI 0.2-1.4, P 0.183), or 90-day favorable outcome (OR 2.0, 95% CI 0.9-4.4, P 0.084).
 
 
 Conclusions:
 In this multicenter study, there was no significant difference in safety and efficacy of MT in patients with MeVOs in posterior circulation (P2 occlusions) compared to M2 and M3 occlusions. Improved techniques for successful recanalization are needed for posterior circulation MeVOs.
 
 
 


Abstract 48: Outcomes And Risk Of Hemorrhagic Transformation Following Mechanical Thrombectomy In Primary Distal Posterior Cerebral Artery Occlusions-subgroup Analysis From STAR

Michael Levitt

Papers

Improving Computational Fluid Dynamics Simulations of Coiled Aneurysms Using Finite Element Modeling

Abstract 48: Outcomes And Risk Of Hemorrhagic Transformation Following Mechanical Thrombectomy In Primary Distal Posterior Cerebral Artery Occlusions-subgroup Analysis From STAR