Pratul K. Agarwal

Oak Ridge National Laboratory, Oak Ridge, Florida, United States

Are you Pratul K. Agarwal?

Claim your profile

Publications (103)194.83 Total impact

  • [Show abstract] [Hide abstract] ABSTRACT: Homotetrameric R67 dihydrofolate reductase possesses 222 symmetry and a single active site pore. This situation results in a promiscuous binding site that accommodates either the substrate, dihydrofolate, or the cofactor, NADPH. NADPH interacts more directly with the protein as it is larger than the substrate. In contrast, the para-aminobenzoyl-glutamate tail of DHF, as monitored by NMR and crystallography, is disordered when bound. To explore whether smaller active site volumes (which should decrease the tail disorder by confinement effects) alter steady state rates, asymmetric mutations were constructed that decreased the half-pore volume by ~35%. Only minor effects on kcat were observed. To continue exploring the role of tail disorder on catalysis, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide mediated crosslinking between R67 DHFR and folate was performed. A two folate:one tetramer complex results in loss of enzyme activity where two symmetry related K32 residues in the protein are crosslinked to the carboxylates of two bound folates. The tethered folate could be reduced, although with a ≤30 fold decreased rate, suggesting decreased dynamics and/or suboptimal positioning of the crosslinked folate for catalysis. Computer simulations that restrain the dihydrofolate tail near K32 indicate that cross-linking still allows movement of the para-aminobenzoyl ring, which allows the reaction to occur. Finally, a bis-ethylene-diamine-α,γ-amide folate adduct was synthesized, where both negatively charged carboxylates in the glutamate tail were replaced by positively charged amines. The Ki for this adduct was ~9 fold higher than for folate. These various results indicate a balance between folate tail disorder, which helps the enzyme bind substrate, while dynamics facilitates catalysis.
    No preview · Article · Dec 2015 · Biochemistry
  • No preview · Article · Jan 2015 · Biophysical Journal
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Functioning proteins do not remain fixed in a unique structure, but instead they sample a range of conformations facilitated by motions within the protein. Even in the native state, a protein exists as a collection of interconverting conformations driven by thermodynamic fluctuations. Motions on the fast time scale allow a protein to sample conformations in the nearby area of its conformational landscape, while motions on slower time scales give it access to conformations in distal areas of the landscape.
    Full-text · Article · Aug 2013 · Accounts of Chemical Research
  • [Show abstract] [Hide abstract] ABSTRACT: Performance improvements in biomolecular simulations based on molecular dynamics (MD) codes are widely desired. Unfortunately, the factors, which allowed past performance improvements, particularly the microprocessor clock frequencies, are no longer increasing. Hence, novel software and hardware solutions are being explored for accelerating performance of widely used MD codes. In this paper, we describe our efforts on porting, optimizing and tuning of Large‐scale Atomic/Molecular Massively Parallel Simulator, a popular MD framework, on heterogeneous architectures: multi‐core processors with graphical processing unit (GPU) accelerators. Our implementation is based on accelerating the most computationally expensive non‐bonded interaction terms on the GPUs and overlapping the computation on the CPU and GPUs. This functionality is built on top of message passing interface that allows multi‐level parallelism to be extracted even at the workstation level with the multi‐core CPUs and allows extension of the implementation on GPU‐enabled clusters. We hypothesize that the optimal benefit of heterogeneous architectures for applications will come by utilizing all possible resources (for example, CPU‐cores and GPU devices on GPU‐enabled clusters). Benchmarks for a range of biomolecular system sizes are provided, and an analysis is performed on four generations of NVIDIA's GPU devices. On GPU‐enabled Linux clusters, by overlapping and pipelining computation and communication, we observe up to 10‐folds application acceleration in multi‐core and multi‐GPU environments illustrating significant performance improvements. Detailed analysis of the implementation is presented that allows identification of bottlenecks in algorithm, indicating that code optimization and improvements on GPUs could allow microsecond scale simulation throughput on workstations and inexpensive GPU clusters, putting widely desired biologically relevant simulation time‐scales within reach of a large user community. In order to systematically optimize simulation throughput and to enable performance prediction, we have developed a parameterized performance model that will allow developers and users to explore the performance potential of future heterogeneous systems for biological simulations. Copyright © 2012 John Wiley & Sons, Ltd.
    No preview · Article · Jul 2013 · Concurrency and Computation Practice and Experience
  • Source
    Pratul K. Agarwal
    Preview · Article · Mar 2013 · Physics of Life Reviews
  • [Show abstract] [Hide abstract] ABSTRACT: Biomolecular simulations at millisecond and longer time-scales can provide vital insights into functional mechanisms. Because post-simulation analyses of such large trajectory datasets can be a limiting factor in obtaining biological insights, there is an emerging need to identify key dynamical events and relating these events to the biological function online, that is, as simulations are progressing. Recently, we have introduced a novel computational technique, quasi-anharmonic analysis (QAA) (Ramanathan et al., PLoS One 2011;6:e15827), for partitioning the conformational landscape into a hierarchy of functionally relevant sub-states. The unique capabilities of QAA are enabled by exploiting anharmonicity in the form of fourth-order statistics for characterizing atomic fluctuations. In this article, we extend QAA for analyzing long time-scale simulations online. In particular, we present HOST4MD-a higher-order statistical toolbox for molecular dynamics simulations, which (1) identifies key dynamical events as simulations are in progress, (2) explores potential sub-states, and (3) identifies conformational transitions that enable the protein to access those sub-states. We demonstrate HOST4MD on microsecond timescale simulations of the enzyme adenylate kinase in its apo state. HOST4MD identifies several conformational events in these simulations, revealing how the intrinsic coupling between the three subdomains (LID, CORE, and NMP) changes during the simulations. Further, it also identifies an inherent asymmetry in the opening/closing of the two binding sites. We anticipate that HOST4MD will provide a powerful and extensible framework for detecting biophysically relevant conformational coordinates from long time-scale simulations. Proteins 2012. © 2012 Wiley Periodicals, Inc.
    No preview · Article · Nov 2012 · Proteins Structure Function and Bioinformatics
  • Pratul K Agarwal
    No preview · Article · Oct 2012 · Physics of Life Reviews
  • [Show abstract] [Hide abstract] ABSTRACT: Ferroelectrics are multifunctional materials that reversibly change their polarization under an electric field. Recently, the search for new ferroelectrics has focused on organic and bio-organic materials, where polarization switching is used to record/retrieve information in the form of ferroelectric domains. This progress has opened a new avenue for data storage, molecular recognition, and new self-assembly routes. Crystalline glycine is the simplest amino acid and is widely used by living organisms to build proteins. Here, it is reported for the first time that γ-glycine, which has been known to be piezoelectric since 1954, is also a ferroelectric, as evidenced by local electromechanical measurements and by the existence of as-grown and switchable ferroelectric domains in microcrystals grown from the solution. The experimental results are rationalized by molecular simulations that establish that the polarization vector in γ-glycine can be switched on the nanoscale level, opening a pathway to novel classes of bioelectronic logic and memory devices.
    No preview · Article · Jul 2012 · Advanced Functional Materials
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: The molten globule nuclear receptor co-activator binding domain (NCBD) of CREB binding protein (CBP) selectively recruits transcription co-activators (TCAs) during the formation of the transcription preinitiation complex. NCBD:TCA interactions have been implicated in several cancers, however, the mechanisms of NCBD:TCA recognition remain uncharacterized. NCBD:TCA intermolecular recognition has challenged traditional investigation as both NCBD and several of its corresponding TCAs are intrinsically disordered. Using 40μs of explicit solvent molecular dynamics simulations, we relate the conformational diversity of ligand-free NCBD to its bound configurations. We introduce two novel techniques to quantify the conformational heterogeneity of ligand-free NCBD, dihedral quasi-anharmonic analysis (dQAA) and hierarchical graph-based diffusive clustering. With this integrated approach we find that three of four ligand-bound states are natively accessible to the ligand-free NCBD simulations with root-mean squared deviation (RMSD) less than 2Å These conformations are accessible via diverse pathways while a rate-limiting barrier must be crossed in order to access the fourth bound state.
    Full-text · Article · May 2012 · Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Enzyme engineering for improved catalysis has wide implications. We describe a novel chemical modification of Candida antarctica lipase B that allows modulation of the enzyme conformation to promote catalysis. Computational modeling was used to identify dynamical enzyme regions that impact the catalytic mechanism. Surface loop regions located distal to active site but showing dynamical coupling to the reaction were connected by a chemical bridge between Lys136 and Pro192, containing a derivative of azobenzene. The conformational modulation of the enzyme was achieved using two sources of light that alternated the azobenzene moiety in cis and trans conformations. Computational model predicted that mechanical energy from the conformational fluctuations facilitate the reaction in the active-site. The results were consistent with predictions as the activity of the engineered enzyme was found to be enhanced with photoactivation. Preliminary estimations indicate that the engineered enzyme achieved 8–52 fold better catalytic activity than the unmodulated enzyme.
    Full-text · Article · May 2012 · Biophysical Journal
  • Source
    Full-text · Article · Jan 2012 · Biophysical Journal
  • Source
    Dataset: Table S6
    Arvind Ramanathan · Pratul K. Agarwal
    [Show abstract] [Hide abstract] ABSTRACT: Network interactions in RNaseA fold. (DOC)
    Preview · Dataset · Nov 2011
  • Source
    Dataset: Movie S5
    Arvind Ramanathan · Pratul K. Agarwal
    [Show abstract] [Hide abstract] ABSTRACT: Mode showing the second highest coupling hydride transfer reaction. For more information, see Text S1. (MPG)
    Preview · Dataset · Nov 2011
  • Source
    Dataset: Movie S3
    Arvind Ramanathan · Pratul K. Agarwal
    [Show abstract] [Hide abstract] ABSTRACT: Mode showing the third highest coupling to cis/trans isomerization reaction. For more information, see Text S1. (MPG)
    Preview · Dataset · Nov 2011
  • Source
    Dataset: Movie S7
    Arvind Ramanathan · Pratul K. Agarwal
    [Show abstract] [Hide abstract] ABSTRACT: RNaseA mode with the lowest eigenvalue. For more information, see Text S1. (MPG)
    Preview · Dataset · Nov 2011
  • Source
    Dataset: Movie S2
    Arvind Ramanathan · Pratul K. Agarwal
    [Show abstract] [Hide abstract] ABSTRACT: Mode showing the second highest coupling to cis/trans isomerization reaction. For more information, see Text S1. (MPG)
    Preview · Dataset · Nov 2011
  • Source
    Dataset: Table S5
    Arvind Ramanathan · Pratul K. Agarwal
    [Show abstract] [Hide abstract] ABSTRACT: RNaseA regions showing high correlations. (DOC)
    Preview · Dataset · Nov 2011
  • Source
    Dataset: Figure S2
    Arvind Ramanathan · Pratul K. Agarwal
    [Show abstract] [Hide abstract] ABSTRACT: Cross-correlations observed along the reaction profile for CypA. B1–B8 correspond to the correlations along the β-sheet of the enzyme. H1–H3 correspond to the three α-helices. Regions marked I1–I4 correspond to distal correlations observed along loop structures. I1: residues 29–33 with 85–86, I2: 34–36 with 77–78, I3: 56–57 with 142–150 and I4: residues 82–85 with 104–108. Note, residue numbers mentioned above refer to H. sapiens as the reference species; corresponding residue numbers for the two species are available in Table S1. (TIF)
    Preview · Dataset · Nov 2011
  • Source
    Dataset: Figure S3
    Arvind Ramanathan · Pratul K. Agarwal
    [Show abstract] [Hide abstract] ABSTRACT: Conservation of the network interactions as a part of PPIase fold: human CypA (I) PDB code: 1RMH; human cyclophilin B (II) PDB code: 1CYN; B. Malayi (III) PDB code: 1A33; B. Taurus (IV) PDB code: 1IHG; E. coli (V) PDB code: 2NUL. The equivalent hydrogen bonds are listed in Table S2. Substrate is shown in orange ball-and-stick model for human CypA. (TIF)
    Preview · Dataset · Nov 2011
  • Source
    Dataset: Table S4
    Arvind Ramanathan · Pratul K. Agarwal
    [Show abstract] [Hide abstract] ABSTRACT: Network interactions in DHFR fold. (DOC)
    Preview · Dataset · Nov 2011

Publication Stats

2k Citations
194.83 Total Impact Points

Institutions

  • 1970-2015
    • Oak Ridge National Laboratory
      • • Computer Science and Mathematics Division
      • • Center for Nanophase Materials Sciences
      Oak Ridge, Florida, United States
  • 2012
    • Carnegie Mellon University
      • Computer Science Department
      Pittsburgh, Pennsylvania, United States
  • 2006
    • Institute Of Computational Biology
      Bengalūru, Karnataka, India
  • 2000
    • Pennsylvania State University
      • Department of Chemistry
      University Park, Maryland, United States
    • University of Notre Dame
      • Department of Chemistry and Biochemistry
      South Bend, Indiana, United States