Scalable molecular dynamics with NAMD on the IBM Blue Gene/L system

Kumar, Sameer; Huang, Chao; Zheng, Gengbin; Bohm, Eric J.; Bhatelé, Abhinav; Phillips, J. C.; Yu, Hao; Kalé, Laxmikant V.

doi:10.1147/rd.521.0177

Cited by 87 publications

(86 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The 100-mM MgCl 2 salt concentration was set up by replacing some water molecules with Mg 2+ and Cl − ions. All our molecular dynamics simulations were performed with the NAMD2 package (44) optimized on an IBM Bluegene supercomputer (45). Molecular dynamics simulations have been widely used to complement experiments (46)(47)(48)(49)(50)(51)(52)(53), which can provide atomic details that are often inaccessible in experiments due to resolution limits, even with the most sophisticated experimental techniques currently available.…”

Section: Methodsmentioning

confidence: 99%

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

Dai

Kang

Huynh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Surface-assisted self-assembly of amyloid-like peptides has received considerable interest in both amyloidosis research and nanotechnology in recent years. Despite extensive studies, some controlling factors, such as salts, are still not well understood, even though it is known that some salts can promote peptide selfassemblies through the so-called "salting-out" effect. However, they are usually noncontrollable, disordered, amorphous aggregates. Here, we show via a combined experimental and theoretical approach that a conserved consensus peptide NH 2 -VGGAVVAGV-CONH 2 (GAV-9) (from representative amyloidogenic proteins) can self-assemble into highly ordered, multilayered nanofilaments, with surprising all-upright conformations, under high-salt concentrations. Our atomic force microscopy images also demonstrate that the vertical stacking of multiple layers is highly controllable by tuning the ionic strength, such as from 0 mM (monolayer) to 100 mM (mainly double layer), and to 250 mM MgCl 2 (double, triple, quadruple, and quintuple layers). Our atomistic molecular dynamics simulations then reveal that these individual layers have very different internal nanostructures, with parallel β-sheets in the first monolayer but antiparallel β-sheets in the subsequent upper layers due to their different microenvironment. Further studies show that the growth of multilayered, all-upright nanostructures is a common phenomenon for GAV-9 at the mica/water interface, under a variety of salt types and a wide range of salt concentrations.amyloid peptide | atomic force microscopy | salt effect | self-assembly on mica A better understanding of the self-assembly of highly ordered peptide nanostructures is critical because it not only helps to uncover the pathogenesis of various neurodegenerative diseases (1) but provides an attractive "bottom-up" nanotechnology for de novo nanodevice design (2) and fabrication (3). In addition to a series of factors (4-6) previously discovered to modulate peptide self-assembly, solid substrates have been found to drive this process directly acting as templates (7,8), controlling both assembly kinetics and morphology of amyloid peptide aggregates (8-11). These findings emphasize the importance of the substrate surface, whether it be a cellular membrane or an inorganic solid surface, on the assembly of various peptides, which is critical in many biological processes. It has been shown recently that fibrous nanostructures form a fundamental framework ubiquitous in normal cellular metabolism, including cell division and signaling, as well as in over 27 different human amyloid diseases and 9 in animals (12).Due to the complexity of cellular membranes and associated physiological conditions (13,14), hydrophilic mica and hydrophobic highly oriented pyrolytic graphite (HOPG) are the two commonly used model substrates for the investigation of surface effects (10,11,15). For example, it was found that amyloid-β (Aβ) peptide formed oligomeric protofibrillar aggregates on mica but only 1D nanofilaments on HOPG (...

show abstract

Section: Methodsmentioning

confidence: 99%

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

Dai

Kang

Huynh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The CHARMM32 (c32b1 parameter set) force field 49 and TIP3P water model 50 was used to run MD. All simulations wee performed using NAMD2 molecular modeling package 51,52 with a 2 fs time step in NPT ensemble at 1atm.…”

Section: System and Methodsmentioning

confidence: 99%

β‐strand interactions at the domain interface critical for the stability of human lens γD‐crystallin

2009

View full text Add to dashboard Cite

Human age-onset cataracts are believed to be caused by the aggregation of partially unfolded or covalently damaged lens crystallin proteins; however, the exact molecular mechanism remains largely unknown. We have used microseconds of molecular dynamics simulations with explicit solvent to investigate the unfolding process of human lens cD-crystallin protein and its isolated domains. A partially unfolded folding intermediate of cD-crystallin is detected in simulations with its C-terminal domain (C-td) folded and N-terminal domain (N-td) unstructured, in excellent agreement with biochemical experiments. Our simulations strongly indicate that the stability and the folding mechanism of the N-td are regulated by the interdomain interactions, consistent with experimental observations. A hydrophobic folding core was identified within the C-td that is comprised of a and b strands from the Greek key motif 4, the one near the domain interface. Detailed analyses reveal a surprising non-native surface salt-bridge between Glu135 and Arg142 located at the end of the ab folded hairpin turn playing a critical role in stabilizing the folding core. On the other hand, an in silico single E135A substitution that disrupts this non-native Glu135-Arg142 salt-bridge causes significant destabilization to the folding core of the isolated C-td, which, in turn, induces unfolding of the N-td interface. These findings indicate that certain highly conserved charged residues, that is, Glu135 and Arg142, of cD-crystallin are crucial for stabilizing its hydrophobic domain interface in native conformation, and disruption of charges on the cD-crystallin surface might lead to unfolding and subsequent aggregation.

show abstract

“…parallel and specially optimized version (for BlueGene/L) of NAMD2 48 is used to perform these FEP simulations. For the mutation of a neutral residue to a charged one, the system charge is counter-balanced by mutating another neutral residue far from the binding site to an oppositely charged one.…”

Section: Methods and Systemmentioning

confidence: 99%

Free energy simulations reveal a double mutant avian H5N1 virus hemagglutinin with altered receptor binding specificity

Das

Royyuru

et al. 2009

J Comput Chem

View full text Add to dashboard Cite

Historically, influenza pandemics have been triggered when an avian influenza virus or a human/avian reassorted virus acquires the ability to replicate efficiently and become transmissible in the human population. Most critically, the major surface glycoprotein hemagglutinin (HA) must adapt to the usage of human-like (alpha-2,6-linked) sialylated glycan receptors. Therefore, identification of mutations that can switch the currently circulating H5N1 HA receptor binding specificity from avian to human might provide leads to the emergence of pandemic H5N1 viruses. To define such mutations in the H5 subtype, here we provide a computational framework that combines molecular modeling with extensive free energy simulations. Our results show that the simulated binding affinities are in good agreement with currently available experimental data. Moreover, we predict that one double mutation (V135S and A138S) in HA significantly enhances alpha-2,6-linked receptor recognition by the H5 subtype. Our simulations indicate that this double mutation in H5N1 HA increases the binding affinity to alpha-2,6-linked sialic acid receptors by 2.6 +/- 0.7 kcal/mol per HA monomer that primarily arises from the electrostatic interactions. Further analyses reveal that introduction of this double mutation results in a conformational change in the receptor binding pocket of H5N1 HA. As a result, a major rearrangement occurs in the hydrogen-bonding network of HA with the human receptor, making the human receptor binding pattern of double mutant H5N1 HA surprisingly similar to that observed in human H1N1 HA. These large scale molecular simulations on single and double mutants thus provide new insights into our understanding toward human adaptation of the avian H5N1 virus.

show abstract

Scalable molecular dynamics with NAMD on the IBM Blue Gene/L system

Cited by 87 publications

References 20 publications

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

β‐strand interactions at the domain interface critical for the stability of human lens γD‐crystallin

Free energy simulations reveal a double mutant avian H5N1 virus hemagglutinin with altered receptor binding specificity

Contact Info

Product

Resources

About