A Suite of Tutorials for the WESTPA 2.0 Rare-Events Sampling Software [Article v2.0].

The weighted ensemble (WE) strategy has been demonstrated to be highly efficient in generating pathways and rate constants for rare events such as protein folding and protein binding using atomistic molecular dynamics simulations. Here we present two sets of tutorials instructing users in the best practices for preparing, carrying out, and analyzing WE simulations for various applications using the WESTPA software. The first set of more basic tutorials describes a range of simulation types, from a molecular association process in explicit solvent to more complex processes such as host-guest association, peptide conformational sampling, and protein folding.

Computational Estimation of Microsecond to Second Atomistic Folding Times.

Despite the development of massively parallel computing hardware including inexpensive graphics processing units (GPUs), it has remained infeasible to simulate the folding of atomistic proteins at room temperature using conventional molecular dynamics (MD) beyond the microsecond scale. Here, we report the folding of atomistic, implicitly solvated protein systems with folding times τ ranging from ∼10 μs to ∼100 ms using the weighted ensemble (WE) strategy in combination with GPU computing. Starting from an initial structure or set of structures, WE organizes an ensemble of GPU-accelerated MD trajectory segments via intermittent pruning and replication events to generate statistically unbiased estimates of rate constants for rare events such as folding; no biasing forces are used.

A Suite of Tutorials for the WESTPA Rare-Events Sampling Software [Article v1.0].

The weighted ensemble (WE) strategy has been demonstrated to be highly efficient in generating pathways and rate constants for rare events such as protein folding and protein binding using atomistic molecular dynamics simulations. Here we present five tutorials instructing users in the best practices for preparing, carrying out, and analyzing WE simulations for various applications using the WESTPA software. Users are expected to already have significant experience with running standard molecular dynamics simulations using the underlying dynamics engine of interest (e.

Nanobubbles, cavitation, shock waves and traumatic brain injury.

Collapse of bubbles, microscopic or nanoscopic, due to their interaction with the impinging pressure wave produces a jet of particles moving in the direction of the wave. If there is a surface nearby, the high-speed jet particles hit it, and as a result damage to the surface is produced. This cavitation effect is well known and intensely studied in case of microscopic sized bubbles.

Behavior of P85 and P188 Poloxamer Molecules: Computer Simulations Using United-Atom Force-Field.

To study the interaction between poloxamer molecules and lipid bilayers using molecular dynamics simulation technique with the united-atom resolution, we augmented the GROMOS force-field to include poloxamers. We validated the force-field by calculating the radii of gyration of two poloxamers, P85 and P188, solvated in water and by considering the poloxamer density distributions at the air/water interface. The emphasis of our simulations was on the study of the interaction between poloxamers and lipid bilayer.

Properties of Poloxamer Molecules and Poloxamer Micelles Dissolved in Water and Next to Lipid Bilayers: Results from Computer Simulations.

To study the properties of poloxamer molecules P85 and P188 and micelles containing these poloxamers in bulk water and also next to lipid bilayers, we performed coarse-grained molecular dynamics computer simulations. We used MARTINI force-field and adjusted Lennard-Jones nonbonded interaction strength parameters for poloxamer beads to take into account the presence of polarizable water. Simulations of systems containing poloxamer molecules or micelles solvated in bulk water showed that structural properties, such as radii of gyration of the molecules and micelles, agree with the ones inferred from experiments.

Opening of the blood-brain barrier tight junction due to shock wave induced bubble collapse: a molecular dynamics simulation study.

Passage of a shock wave across living organisms may produce bubbles in the blood vessels and capillaries. It was suggested that collapse of these bubbles imposed by an impinging shock wave can be responsible for the damage or even destruction of the blood-brain barrier. To check this possibility, we performed molecular dynamics computer simulations on systems that contained a model of tight junction from the blood-brain barrier.

Mechanism of membrane poration by shock wave induced nanobubble collapse: a molecular dynamics study.

We performed coarse-grained molecular dynamics simulations in order to understand the mechanism of membrane poration by shock wave induced nanobubble collapse. Pressure profiles obtained from the simulations show that the shock wave initially hits the membrane and is followed by a nanojet produced by the nanobubble collapse. While in the absence of the nanobubble, the shock wave with an impulse of up to 18 mPa s does not create a pore in the membrane, in the presence of a nanobubble even a smaller impulse leads to the poration of the membrane.

Manipulating unconventional CH-based hydrogen bonding in a methyltransferase via noncanonical amino acid mutagenesis.

Recent studies have demonstrated that the active sites of S-adenosylmethionine (AdoMet)-dependent methyltransferases form strong carbon-oxygen (CH···O) hydrogen bonds with the substrate's sulfonium group that are important in AdoMet binding and catalysis. To probe these interactions, we substituted the noncanonical amino acid p-aminophenylalanine (pAF) for the active site tyrosine in the lysine methyltransferase SET7/9, which forms multiple CH···O hydrogen bonds to AdoMet and is invariant in SET domain enzymes. Using quantum chemistry calculations to predict the mutation's effects, coupled with biochemical and structural studies, we observed that pAF forms a strong CH···N hydrogen bond to AdoMet that is offset by an energetically unfavorable amine group rotamer within the SET7/9 active site that hinders AdoMet binding and activity.

Effects of charge and substituent on the S···N chalcogen bond.

Neutral complexes containing a S···N chalcogen bond are compared with similar systems in which a positive charge has been added to the S-containing electron acceptor, using high-level ab initio calculations. The effects on both XS···N and XS(+)···N bonds are evaluated for a range of different substituents X = CH3, CF3, NH2, NO2, OH, Cl, and F, using NH3 as the common electron donor. The binding energy of XMeS···NH3 varies between 2.

Conservation and functional importance of carbon-oxygen hydrogen bonding in AdoMet-dependent methyltransferases.

S-adenosylmethionine (AdoMet)-based methylation is integral to metabolism and signaling. AdoMet-dependent methyltransferases belong to multiple distinct classes and share a catalytic mechanism that arose through convergent evolution; however, fundamental determinants underlying this shared methyl transfer mechanism remain undefined. A survey of high-resolution crystal structures reveals that unconventional carbon-oxygen (CH···O) hydrogen bonds coordinate the AdoMet methyl group in different methyltransferases irrespective of their class, active site structure, or cofactor binding conformation.

Magnitude and mechanism of charge enhancement of CH··O hydrogen bonds.

Quantum calculations find that neutral methylamines and thioethers form complexes, with N-methylacetamide (NMA) as proton acceptor, with binding energies of 2-5 kcal/mol. This interaction is magnified by a factor of 4-9, bringing the binding energy up to as much as 20 kcal/mol, when a CH3(+) group is added to the proton donor. Complexes prefer trifurcated arrangements, wherein three separate methyl groups donate a proton to the O acceptor.

First steps in growth of a polypeptide toward β-sheet structure.

The full conformational energy surface is examined for a molecule in which a dipeptide is attached to the same spacer group as another peptide chain, so as to model the seminal steps of β-sheet formation. This surface is compared with the geometrical preferences of the isolated dipeptide to extract the perturbations induced by interactions with the second peptide strand. These interpeptide interactions remove any tendency of the dipeptide to form a C5 ring structure, one of its two normally stable geometries.

Preferred configurations of peptide-peptide interactions.

The natural and fundamental proclivities of interaction between a pair of peptide units are examined using high-level ab initio calculations. The NH···O H-bonded structure is found to be the most stable configuration of the N-methylacetamide (NMA) model dimer, but only slightly more so than a stacked arrangement. The H-bonded geometry is destabilized by only a small amount if the NH group is lifted out of the plane of the proton-accepting amide.

Contributions of various noncovalent bonds to the interaction between an amide and S-containing molecules.

N-Methylacetamide, a model of the peptide unit in proteins, is allowed to interact with CH(3) SH, CH(3)SCH(3), and CH(3)SSCH(3) as models of S-containing amino acid residues. All of the minima are located on the ab initio potential energy surface of each heterodimer. Analysis of the forces holding each complex together identifies a variety of different attractive forces, including SH⋅⋅⋅O, NH⋅⋅⋅S, CH⋅⋅⋅O, CH⋅⋅⋅S, SH⋅⋅⋅π, and CH⋅⋅⋅π H-bonds.

Substituent effects on CL···N, S···N, and P···N noncovalent bonds.

Cl, S, and P atoms have previously been shown as capable of engaging in a noncovalent bond with the N atom on another molecule. The effects of substituents B on the former atoms on the strength of this bond are examined, and it is found that the binding energy climbs in the order B = CH(3) < NH(2) < CF(3) < OH < Cl < NO(2) < F. However, there is some variability in this pattern, particularly for the NO(2) group.

Comparison of P···D (D = P,N) with other noncovalent bonds in molecular aggregates.

All the minima on the potential energy surfaces of homotrimers and tetramers of PH(3) are identified and analyzed as to the source of their stability. The same is done with mixed trimers in which one PH(3) molecule is replaced by either NH(3) or PFH(2). The primary noncovalent attraction in all global minima is the BP···D (D = N,P) bond which is characterized by the transfer of charge from a lone pair of the donor D to a σ∗ B-P antibond of the partner molecule which is turned away from D, the same force earlier identified in the pertinent dimers.

Abilities of different electron donors (D) to engage in a P···D noncovalent interaction.

Previous work has documented the ability of the P atom to form a direct attractive noncovalent interaction with a N atom, based in large measure on the charge transfer from the N lone pair into the σ* antibonding orbital of the P-H that is turned away from the N atom. The present work considers whether other atoms, namely, O and S, can also participate as electron donors, and in which bonding environments. Also considered are the π-systems of multiply bonded C atoms.