Narayanaswamy Srinivasan

Meenakshi Mission Hospital and Research Centre

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Ramanathan Sowdhamini

National Centre for Biological Sciences

Sankaran Sandhya

University of Petroleum and Energy Studies

Alexandre G. de Brevern

Université Paris Cité

Ramachandra M. Bhaskara

Goethe University Frankfurt

Nagasuma Chandra

Indian Institute of Science Bangalore

Sohini Chakraborti

Indian Institute of Science Bangalore

Agnel Praveen Joseph

Science and Technology Facilities Council

Bernard Offmann

Unité en Sciences Biologiques et Biotechnologies de Nantes

Himani Tandon

Indian Institute of Science Bangalore

Gayatri Ramakrishnan

Radboud University Medical Center

Cooperative Institutions

Indian Institute of Science Bangalore

212

Inserm

National Centre for Biological Sciences

University of Cambridge

Centre National de la Recherche Scientifique

Council of Scientific and Industrial Research

Tata Consultancy Services (India)

Université Paris Cité

National Institutes of Health

Harvard University

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Use of evolutionary information in the fitting of atomic level protein models in low resolution cryo-EM map of a protein assembly improves the accuracy of the fitting

Journal of Structural Biology (2016)

Agnel Praveen Joseph Lakshmipuram S. Swapna Ramachandran Rakesh Narayanaswamy Srinivasan

Interface (matter)

Cryo-Electron Microscopy

Low resolution

10.1016/j.jsb.2016.07.012

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Citations (9)

Identification of Local Conformational Similarity in Structurally Variable Regions of Homologous Proteins Using Protein Blocks

PLoS ONE (2011)

Garima Agarwal Swapnil Mahajan Narayanaswamy Srinivasan Alexandre G. de Brevern

Structure comparison tools can be used to align related protein structures to identify structurally conserved and variable regions and to infer functional and evolutionary relationships. While the conserved regions often superimpose well, the variable regions appear non superimposable. Differences in homologous protein structures are thought to be due to evolutionary plasticity to accommodate diverged sequences during evolution. One of the kinds of differences between 3-D structures of homologous proteins is rigid body displacement. A glaring example is not well superimposed equivalent regions of homologous proteins corresponding to α-helical conformation with different spatial orientations. In a rigid body superimposition, these regions would appear variable although they may contain local similarity. Also, due to high spatial deviation in the variable region, one-to-one correspondence at the residue level cannot be determined accurately. Another kind of difference is conformational variability and the most common example is topologically equivalent loops of two homologues but with different conformations. In the current study, we present a refined view of the "structurally variable" regions which may contain local similarity obscured in global alignment of homologous protein structures. As structural alphabet is able to describe local structures of proteins precisely through Protein Blocks approach, conformational similarity has been identified in a substantial number of 'variable' regions in a large data set of protein structural alignments; optimal residue-residue equivalences could be achieved on the basis of Protein Blocks which led to improved local alignments. Also, through an example, we have demonstrated how the additional information on local backbone structures through protein blocks can aid in comparative modeling of a loop region. In addition, understanding on sequence-structure relationships can be enhanced through our approach. This has been illustrated through examples where the equivalent regions in homologous protein structures share sequence similarity to varied extent but do not preserve local structure.

Protein superfamily

Structural alignment

Similarity (geometry)

10.1371/journal.pone.0017826

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Citations (7)

Long‐range molecular dynamics show that inactive forms of Protein Kinase A are more dynamic than active forms

Protein Science (2018)

Raju Kalaivani Tarun Narwani Alexandre G. de Brevern Narayanaswamy Srinivasan

Many protein kinases are characterized by at least two structural forms corresponding to the highest level of activity (active) and low or no activity, (inactive). Further, protein dynamics is an important consideration in understanding the molecular and mechanistic basis of enzyme function. In this work, we use protein kinase A (PKA) as the model system and perform microsecond range molecular dynamics (MD) simulations on six variants which differ from one another in terms of active and inactive form, with or without bound ligands, C-terminal tail and phosphorylation at the activation loop. We find that the root mean square fluctuations in the MD simulations are generally higher for the inactive forms than the active forms. This difference is statistically significant. The higher dynamics of inactive states has significant contributions from ATP binding loop, catalytic loop, and αG helix. Simulations with and without C-terminal tail show this differential dynamics as well, with lower dynamics both in the active and inactive forms if C-terminal tail is present. Similarly, the dynamics associated with the inactive form is higher irrespective of the phosphorylation status of Thr 197. A relatively stable stature of active kinases may be better suited for binding of substrates and detachment of the product. Also, phosphoryl group transfer from ATP to the phosphosite on the substrate requires precise transient coordination of chemical entities from three different molecules, which may be facilitated by the higher stability of the active state.

Protein Dynamics

Dynamics

10.1002/pro.3556

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Citations (10)

Author response for "How good are comparative models in the understanding of protein dynamics?"

Arangasamy Yazhini Narayanaswamy Srinivasan

Dynamics

10.1002/prot.25879/v2/response1

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Single-Site Phosphorylation Elicits Structural, Dynamic, and Accessibility Changes in Proteins at both Proximal and Distal Regions to the Phosphosite

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Seemadri Subhadarshini Himani Tandon Narayanaswamy Srinivasan Ramanathan Sowdhamini

ABSTRACT Phosphorylation, a fundamental cellular mechanism, intricately regulates protein function and signaling pathways. Our study employs extensive computational analyses on a curated dataset of phosphorylated and unphosphorylated protein structures to explore the multifaceted impact of phosphorylation on protein conformation. Our findings reveal that phosphorylation induces not only local changes at the phosphorylation site but also extensive alterations in distant regions, showcasing its far-reaching influence on protein structure-dynamics. Using Normal Mode Analysis (NMA), we investigate changes in protein flexibility post-phosphorylation, highlighting an enhanced level of structural dynamism. Through in-depth case studies on Polyubiquitin-B and Glycogen Synthase Kinase-3 Beta, we elucidate how phosphorylation at distinct sites leads to variable structural and dynamic modifications, potentially dictating functional outcomes. While phosphorylation largely preserves residue motion correlation, it significantly disrupts low-frequency global modes, presenting a dualistic impact on protein dynamics. We also explore alterations in the total accessible surface area (ASA), emphasizing region-specific changes around phosphorylation sites. This study sheds light on phosphorylation-induced conformational changes, dynamic modulation, and surface accessibility alterations, contributing to a comprehensive understanding of cellular regulation and suggesting promising avenues for therapeutic interventions.

Phosphorylation cascade

10.1101/2023.11.30.569386

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Citations (0)

MOESM1 of Exploring anti-malarial potential of FDA approved drugs: an in silico approach

Figshare (2017)

Gayatri Ramakrishnan Nagasuma Chandra Narayanaswamy Srinivasan

Additional file 1. Details on drug-target associations predicted for Plasmodium falciparum.

10.6084/m9.figshare.c.3830056_d1

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Functional characterization and structural modelling of late gene expression factor 4 from Bombyx mori nucleopolyhedrovirus

Biochemical Journal (2002)

Seema Sehrawat Narayanaswamy Srinivasan Karumathil P. Gopinathan

Late gene expression factor 4 (LEF4), a multifunctional protein encoded by the Bombyx mori nucleopolyhedrovirus has been bacterially expressed and characterized. Sequence analyses and three-dimensional modelling of B. mori LEF4 showed that the protein is related to mRNA-capping enzymes, which are organized as two modular domains. Most of the acidic side chains in LEF4 were solvent-exposed and spread all along the fold. A region dominated by negatively charged groups, which protrudes from the larger domain was ideally suited for interactions with proteins having positively charged patches at the surface. The purified LEF4 protein exhibited different enzyme activities associated with mRNA-capping enzymes, i.e. GTP-binding, RNA triphosphatase and guanylate transferase activities. In addition, LEF4 also showed NTP-hydrolysing activity. The kinetic analysis of ATP hydrolysis revealed a sigmoidal response with two deduced binding sites for ATP, whereas the guanylate transferase activity showed a typical hyperbolic response to varying concentrations of GTP with a Km of 330+/-20 microM. Analysis of the modelled three-dimensional structure of LEF4 suggested the presence of crucial residues in sequence motifs important for the integrity of the fold. Mutation of one such conserved and buried tyrosine residue to cysteine in the motif IIIa, located close to the interlobe region of the model, resulted in a 44% loss of guanylate transferase activity of LEF4 but had no effect on the ATPase activity.

Transferase

10.1042/bj20020456

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Citations (3)

Additional file 1: of Interface residues of transient protein-protein complexes have extensive intra-protein interactions apart from inter-protein interactions

Figshare (2019)

Srinivasan Jayashree Pavalam Murugavel Ramanathan Sowdhamini Narayanaswamy Srinivasan

Table S1. List of transient protein-protein complexes used in the analysis (shown in green colour). PDB code of the unbound form of protein 1 is shown in pink. Where available, the PDB code of the unbound form of the second subunit is also noted (as shown in blue colour). (XLSX 16 kb)

Transient (computer programming)

Interface (matter)

10.6084/m9.figshare.7591847

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Citations (0)

Interfacial residues in protein-protein complexes are in the eyes of the beholder

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Jayadevan Parvathy Arangasamy Yazhini Narayanaswamy Srinivasan Ramanathan Sowdhamini

Abstract Interactions between proteins are vital in almost all biological processes. The characterization of protein-protein interactions helps us understand the mechanistic basis of biological processes, thereby enabling the manipulation of proteins for biotechnological and clinical purposes. The interface residues of a protein-protein complex are assumed to have the following two properties: a) they always interact with a residue of a partner protein, which forms the basis for distance-based interface residue identification methods, and b) they are solvent-exposed in the isolated form of the protein and become buried in the complex form, which forms the basis for Accessible Surface Area (ASA)-based methods. The study interrogates this popular assumption by recognizing interface residues in protein-protein complexes through these two methods. The study shows that a few residues are identified uniquely by each method, and the extent of conservation, propensities and their contribution to the stability of protein-protein interaction varies substantially between these residues. The case study analyses showed that interface residues, unique to distance, participate in crucial interactions that hold the proteins together, whereas the interface residues unique to the ASA method have a potential role in the recognition, dynamics and specificity of the complex and can also be a hotspot. Overall, the study recommends applying both distance and ASA methods so that some interface residues missed by either method but crucial to the stability, recognition, dynamics and function of protein-protein complexes are identified in a complementary manner.

Residue (chemistry)

Surface protein

10.1101/2023.04.24.538134

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Cascade PSI-BLAST web server: a remote homology search tool for relating protein domains

Nucleic Acids Research (2006)

R K Bhadra Sankaran Sandhya K. R. Abhinandan Shaon Chakrabarti Ramanathan Sowdhamini

Owing to high evolutionary divergence, it is not always possible to identify distantly related protein domains by sequence search techniques. Intermediate sequences possess sequence features of more than one protein and facilitate detection of remotely related proteins. We have demonstrated recently the employment of Cascade PSI-BLAST where we perform PSI-BLAST for many ‘generations’, initiating searches from new homologues as well. Such a rigorous propagation through generations of PSI-BLAST employs effectively the role of intermediates in detecting distant similarities between proteins. This approach has been tested on a large number of folds and its performance in detecting superfamily level relationships is ∼35% better than simple PSI-BLAST searches. We present a web server for this search method that permits users to perform Cascade PSI-BLAST searches against the Pfam, SCOP and SwissProt databases. The URL for this server is http://crick.mbu.iisc.ernet.in/~CASCADE/CascadeBlast.html .

Sequence homology

Homology

Sequence (biology)

Multiple sequence alignment

10.1093/nar/gkl157

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Citations (16)