PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data

We describe PTRAJ and its successor CPPTRAJ, two complementary, portable, and freely available computer programs for the analysis and processing of time series of three-dimensional atomic positions (i.e., coordinate trajectories) and the data therein derived. Common tools include the ability to manipulate the data to convert among trajectory formats, process groups of trajectories generated with ensemble methods (e.g., replica exchange molecular dynamics), image with periodic boundary conditions, create average structures, strip subsets of the system, and perform calculations such as RMS fitting, measuring distances, B-factors, radii of gyration, radial distribution functions, and time correlations, among other actions and analyses. Both the PTRAJ and CPPTRAJ programs and source code are freely available under the GNU General Public License version 3 and are currently distributed within the AmberTools 12 suite of support programs that make up part of the Amber package of computer programs (see http://ambermd.org). This overview describes the general design, features, and history of these two programs, as well as algorithmic improvements and new features available in CPPTRAJ

Improved Generalized Born Solvent Model Parameters for Protein Simulations

The generalized Born (GB) model is one of the fastest implicit solvent models, and it has become widely adopted for Molecular Dynamics (MD) simulations. This speed comes with trade-offs, and many reports in the literature have pointed out weaknesses with GB models. Because the quality of a GB model is heavily affected by empirical parameters used in calculating solvation energy, in this work we have refit these parameters for GB-Neck, a recently developed GB model, in order to improve the accuracy of both the solvation energy and effective radii calculations. The data sets used for fitting are significantly larger than those used in the past. Comparing to other pairwise GB models like GB-OBC and the original GB-Neck, the new GB model (GB-Neck2) has better agreement with Poisson–Boltzmann (PB) in terms of reproducing solvation energies for a variety of systems ranging from peptides to proteins. Secondary structure preferences are also in much better agreement with those obtained from explicit solvent MD simulations. We also obtain near-quantitative reproduction of experimental structure and thermal stability profiles for several model peptides with varying secondary structure motifs. Extension to nonprotein systems will be explored in the future

Reliable Oligonucleotide Conformational Ensemble Generation in Explicit Solvent for Force Field Assessment Using Reservoir Replica Exchange Molecular Dynamics Simulations

Molecular dynamics force field development and assessment requires a reliable means for obtaining a well-converged conformational ensemble of a molecule in both a time-efficient and cost-effective manner. This remains a challenge for RNA because its rugged energy landscape results in slow conformational sampling and accurate results typically require explicit solvent which increases computational cost. To address this, we performed both traditional and modified replica exchange molecular dynamics simulations on a test system (alanine dipeptide) and an RNA tetramer known to populate A-form-like conformations in solution (single-stranded rGACC). A key focus is on providing the means to demonstrate that convergence is obtained, for example, by investigating replica RMSD profiles and/or detailed ensemble analysis through clustering. We found that traditional replica exchange simulations still require prohibitive time and resource expenditures, even when using GPU accelerated hardware, and our results are not well converged even at 2 μs of simulation time per replica. In contrast, a modified version of replica exchange, reservoir replica exchange in explicit solvent, showed much better convergence and proved to be both a cost-effective and reliable alternative to the traditional approach. We expect this method will be attractive for future research that requires quantitative conformational analysis from explicitly solvated simulations

Computational Assessment of Potassium and Magnesium Ion Binding to a Buried Pocket in GTPase-Associating Center RNA

An experimentally well-studied model of RNA tertiary structures is a 58mer rRNA fragment, known as GTPase-associating center (GAC) RNA, in which a highly negative pocket walled by phosphate oxygen atoms is stabilized by a chelated cation. Although such deep pockets with more than one direct phosphate to ion chelation site normally include magnesium, as shown in one GAC crystal structure, another GAC crystal structure and solution experiments suggest potassium at this site. Both crystal structures also depict two magnesium ions directly bound to the phosphate groups comprising this controversial pocket. Here, we used classical molecular dynamics simulations as well as umbrella sampling to investigate the possibility of binding of potassium versus magnesium inside the pocket and to better characterize the chelation of one of the binding magnesium ions outside the pocket. The results support the preference of the pocket to accommodate potassium rather than magnesium and suggest that one of the closely binding magnesium ions can only bind at high magnesium concentrations, such as might be present during crystallization. This work illustrates the complementary utility of molecular modeling approaches with atomic-level detail in resolving discrepancies between conflicting experimental results

Self-Tensioning Aquatic Caddisfly Silk: Ca²⁺-Dependent Structure, Strength, and Load Cycle Hysteresis

Caddisflies are aquatic relatives of silk-spinning terrestrial moths and butterflies. Casemaker larvae spin adhesive silk fibers for underwater construction of protective composite cases. The central region of Hesperophylax sp. H-fibroin contains a repeating pattern of three conserved subrepeats, all of which contain one or more (SX)_<i>n</i> motifs with extensively phosphorylated serines. Native silk fibers were highly extensible and displayed a distinct yield point, force plateau, and load cycle hysteresis. FTIR spectroscopy of native silk showed a conformational mix of random coil, β-sheet, and turns. Exchanging multivalent ions with Na⁺ EDTA disrupted fiber mechanics, shifted the secondary structure ratios from antiparallel β-sheet toward random coil and turns, and caused the fibers to shorten, swell in diameter, and disrupted fiber birefringence. The EDTA effects were reversed by restoring Ca²⁺. Molecular dynamic simulations provided theoretical support for a hypothetical structure in which the (pSX)_<i>n</i> motifs may assemble into two- and three-stranded, Ca²⁺-stabilized β-sheets