Pradhan Mohan

Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket

Published date : 15 Jan 2019

The DNA binding domain (DBD) of the tumor suppressor p53 is the site of several oncogenic mutations. A subset of these mutations lowers the unfolding temperature of the DBD. Unfolding leads to the exposure of a hydrophobic β-strand and nucleates aggregation which results in pathologies through loss of function and dominant negative/gain of function effects.

type
Journal Paper
journal
Nuclei Acids Research, 2019, doi: 10.1093/nar/gky1314
Impact Factor
11.561

The interfacial character of antibody paratopes: analysis of antibody-antigen structures

Published date : 16 Jun 2017

In this study, computational methods are applied to investigate the general properties of antigen engaging residues of a paratope from a non-redundant dataset of 403 antibody-antigen complexes to dissect the contribution of hydrogen bonds, hydrophobic, van der Waals contacts and ionic interactions, as well as role of water molecules in the antigen-antibody interface. Consistent with previous reports using smaller datasets, we found that Tyr, Trp, Ser, Asn, Asp, Thr, Arg, Gly, His contribute substantially to the interactions between antibody and antigen.

type
Journal Paper
journal
Bioinformatics, 2017, doi: 10.1093/bioinformatics/btx389
Impact Factor
7.307

Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib

Published date : 08 May 2017

Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket.

type
Journal Paper
journal
Scientific Reports 7, Article no: 1540 (2017), doi:10.1038/s41598-017-01491-z
Impact Factor
4.259

Water-Bridge Mediates Recognition of mRNA Cap in eIF4E

Published date : 01 Dec 2016

Ligand binding pockets in proteins contain water molecules, which play important roles in modulating protein-ligand interactions. Available crystallographic data for the 5′ mRNA cap-binding pocket of the translation initiation factor protein eIF4E shows several structurally conserved waters, which also persist in molecular dynamics simulations. These waters engage an intricate hydrogen-bond network between the cap and protein.

type
Journal Paper
journal
Structure 25, 1–7, January 3, 2017
Impact Factor
5.237

Wetting of non-conserved residue-backbones: A feature indicative of aggregation associated regions of proteins

Published date : 17 Dec 2015

Aggregation is an irreversible form of protein complexation and often toxic to cells. The process entails partial or major unfolding that is largely driven by hydration. We model the role of hydration in aggregation using ‘Dehydrons'. ‘Dehydrons' are unsatisfied backbone hydrogen bonds in proteins that seek shielding from water molecules by associating with ligands or proteins. We find that the residues at aggregation interfaces have hydrated backbones, and in contrast to other forms of protein-protein interactions, are under less evolutionary pressure to be conserved.

type
Journal Paper
journal
Proteins. 2015 Dec 17. doi: 10.1002/prot.24976
Impact Factor
2.627