Solvents to Fragments to Drugs: MD Applications in Drug Design

Simulations of molecular dynamics (MD) are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: Binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals solvent structures and preferential interaction sites (hot spots) on the protein surface. The information provided by water and its cosolvents can be used very effectively to understand protein ligand recognition and to improve the predictive capability of well-established methods such as molecular docking. The application of MD simulations to the study of the association of proteins with drug-like compounds is currently only possible for specific cases, as it remains computationally very expensive and labor intensive. MDmix simulations on the other hand, can be used systematically to address some of the common tasks in SBDD. With the advent of new tools and faster computers we expect to see an increase in the application of mixed solvent MD simulations to a plethora of protein targets to identify new drug candidates

Structural basis for the Pr-Pfr long-range signaling mechanism of a full-length bacterial phytochrome at the atomic level

Phytochromes constitute a widespread photoreceptor family that typically interconverts between two photostates called Pr (red light–absorbing) and Pfr (far-red light–absorbing). The lack of full-length structures solved at the (near-)atomic level in both pure Pr and Pfr states leaves gaps in the structural mechanisms involved in the signal transmission pathways during the photoconversion. Here, we present the crystallographic structures of three versions from the plant pathogen Xanthomonas campestris virulence regulator XccBphP bacteriophytochrome, including two full-length proteins, in the Pr and Pfr states. The structures show a reorganization of the interaction networks within and around the chromophore-binding pocket, an α-helix/β-sheet tongue transition, and specific domain reorientations, along with interchanging kinks and breaks at the helical spine as a result of the photoswitching, which subsequently affect the quaternary assembly. These structural findings, combined with multidisciplinary studies, allow us to describe the signaling mechanism of a full-length bacterial phytochrome at the atomic level.DFG, 221545957, SFB 1078: Proteinfunktion durch ProtonierungsdynamikEC/H2020/664726/EU/EMBL Interdisciplinary, International and Intersectorial Postdocs/EI3PO

Role of cyclic sulfenyl amide formation in protein regulation and protection from overoxidation.

<p>Role of cyclic sulfenyl amide formation in protein regulation and protection from overoxidation.</p

Cyclic sulfenyl amide product structure and its consequences to the reactions occurrence.

<p>A) Top view of the cyclic sulfenyl amide psi dihedral angle. (B) Lateral view of the cyclic sulfenyl amide product with a -155° psi dihedral angle. (C) Lateral view of the cyclic sulfenyl amide product with a -105° psi dihedral angle</p

Protein topology for each relevant Pfam family (in parenthesis the PDBid of the corresponding protein) and protein fold.

<p>PF00102 (1P15), PF00117 (2VPI), PF00581 (3D1P), PF00782 (1D5R), PF00795 (2PLQ), PF01174 (2YWJ) and PF01965 (1PDW)</p

Structural and energetic parameters for the sulfenyl amide formation in PTP1B.

<p>Structural and energetic parameters for the sulfenyl amide formation in PTP1B.</p

Analyses of fold and oxidation detection in PFAM families.

<p>Statistical analysis of proteins in a given family (as defined by PFAM) that display the strand-loop-helix motif with the corresponding Cysteine in the forbidden-psi conformation. The last column “Exp. Info. Oxidation.” shows whether experimental information concerning Cysteine oxidation has been reported in any protein of the PFAM family.</p><p>Analyses of fold and oxidation detection in PFAM families.</p

Molecular Dynamics Simulations Provide Atomistic Insight into Hydrogen Exchange Mass Spectrometry Experiments

It is now clear that proteins are flexible entities that in solution switch between conformations to achieve their function. Hydrogen/Deuterium Exchange Mass Spectrometry (HX/MS) is an invaluable tool to understand dynamic changes in proteins modulated by cofactor binding, post-transductional modifications, or protein–protein interactions. ERK2MAPK, a protein involved in highly conserved signal transduction pathways of paramount importance for normal cellular function, has been extensively studied by HX/MS. Experiments of the ERK2MAPK in the inactive and active states (in the presence or absence of bound ATP) have provided valuable information on the plasticity of the MAPK domain. However, interpretation of the HX/MS data is difficult, and changes are mostly explained in relation to available X-ray structures, precluding a complete atomic picture of protein dynamics. In the present work, we have used all atom Molecular Dynamics simulations (MD) to provide a theoretical framework for the interpretation of HX/MS data. Our results show that detailed analysis of protein–solvent interaction along the MD simulations allows (i) prediction of the number of protons exchanged for each peptide in the HX/MS experiments, (ii) rationalization of the experimentally observed changes in exchange rates in different protein conditions at the residue level, and (iii) that at least for ERK2MAPK, most of the functionally observed differences in protein dynamics are related to what can be considered the native state conformational ensemble. In summary, the combination of HX/MS experiments with all atom MD simulations emerges as a powerful approach to study protein native state dynamics with atomic resolution

A whole genome bioinformatic approach to determine potential latent phase specific targets in Mycobacterium tuberculosis

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-07-07T16:18:51Z No. of bitstreams: 1 Defelipe LA A whole genome.pdf: 2551463 bytes, checksum: 9b2a7bb2e8e75abeb1f6bb886d4e079e (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-07-07T16:30:32Z (GMT) No. of bitstreams: 1 Defelipe LA A whole genome.pdf: 2551463 bytes, checksum: 9b2a7bb2e8e75abeb1f6bb886d4e079e (MD5)Made available in DSpace on 2016-07-07T16:30:32Z (GMT). No. of bitstreams: 1 Defelipe LA A whole genome.pdf: 2551463 bytes, checksum: 9b2a7bb2e8e75abeb1f6bb886d4e079e (MD5) Previous issue date: 2016Made available in DSpace on 2016-07-08T18:41:58Z (GMT). No. of bitstreams: 3 Defelipe LA A whole genome.pdf.txt: 72857 bytes, checksum: 6f5d198733e0f50e22fc5d78d02cc9aa (MD5) Defelipe LA A whole genome.pdf: 2551463 bytes, checksum: 9b2a7bb2e8e75abeb1f6bb886d4e079e (MD5) license.txt: 2991 bytes, checksum: 5a560609d32a3863062d77ff32785d58 (MD5) Previous issue date: 2016Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biologica. Buenos Aires, ArgentinaInstituto de C alculo. Facultad de Ciencias Exactas y Naturales. Plataforma de Bioinformatica Argentina. Buenos Aires, ArgentinaFundação Gonçalo Moniz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Laboratório Nacional de Computação Científica. Petrópolis, RJ, BrasilLaboratório Nacional de Computação Científica. Petrópolis, RJ, BrasilInstituto de Calculo. Facultad de Ciencias Exactas y Naturales. Plataforma de Bioinformatica Argentina. Buenos Aires, ArgentinaUniversidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biologica. Buenos Aires, ArgentinaUniversidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biologica. Buenos Aires, ArgentinaUniversidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biologica. Buenos Aires, ArgentinaUniversidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biologica. Buenos Aires, ArgentinaCurrent Tuberculosis treatment is long and expensive, faces the increasing burden of MDR/XDR strains and lack of effective treatment against latent form, resulting in an urgent need of new anti-TB drugs. Key to TB biology is its capacity to fight the host's RNOS mediated attack. RNOS are known to display a concentration dependent mycobactericidal activity, which leads to the following hypothesis ”if we know which proteins are targeted by RNOS and kill TB, we we might be able to inhibit them with drugs resulting in a synergistic bactericidal effect”. Based on this idea, we performed an Mtb metabolic network whole proteome analysis of potential RNOS sensitive and relevant targets which includes target druggability and essentiality criteria. Our results, available at http://tuberq.proteinq.com.ar yield new potential TB targets, like I3PS, while also providing and updated view of previous proposals becoming an important tool for researchers looking for new ways of killing T