Laboratory of Computational Chemistry and Biochemistry
Institute of Chemical Sciences and Engineering
Swiss Federal Institute of Technology EPF Lausanne
Name: Roberto Dias Lins Neto
Date of Birth: July 20, 1971
Address: Laboratory of Computational Chemistry and Biochemistry
BCH 4107 - EPFL
CH-1015 Lausanne, Switzerland
Phone: +41 (021) 693 0325
FAX: +41 (021) 693 0320
-B.Sc. Biological Sciences, Universidade Federal de Pernambuco, Brazil (03/1991-12/1994)
Advisor: Dr. R. Ferreira.
-Ph.D. Chemistry, Universidade Federal de Pernambuco, Brazil / University of California, San Diego, USA (03/1995-07/1999). Thesis entitled: Structural and Functional Dynamics of the Catalytic Domain of the HIV-1 Integrase. Advisors: Drs. R. Ferreira, J. A. McCammon.
-Visits to University of Houston, Jim Briggs' group (12/1198-06/1999).
-Visiting Assistant Professor at the Department of Biology and Biochemistry, University of Houston (08/1999-02/2000).
-Postdoctoral fellow (shortly) at PNNL, T.P. Straatsma's group (03-11/2000).
-Postdoctoral fellow at ETH-Zurich, Phil Hunenberger's group (12/2000-07/2003).
RESEARCH INTERESTS (according publication list)
1. Computer simulation of proteins
1.1. Analysis of protein dynamics, fluctuations and internal motions.
A number of biological mechanisms, such as catalysis, molecular recognition, folding, molecular transport, etc, are quite often governed by biomolecular dynamics. Therefore, the study of protein dynamics at its different levels is indispensable for the complete understanding of some these properties. The concerted use of molecular, Brownian and essential dynamics on the catalytic domain of the HIV-1 integrase accompanied of a detailed analysis have revealed important structural and functional aspects of this enzyme. Some of the major findings include location the of metal ions in the active site, prediction of secondary structure transition, active site stability metal ion dependent and slow motion gating-type dynamics in a catalytically relevant loop of a of the HIV-1 integrase.
1.2. Protein interactions
Antibody-protein interactions, protein multimerization, drug binding/affinity, solvation properties, etc, constitute a wide and common interest among biologists, chemists, pharmacists and biophysicists. A proper account of electrostatics plays a major role in the description of inter-molecular interactions. Efficient methods and algorithms allowing large sampling and relative free energy computing are a plus. Here the HIV-1 integrase is used again as an example. From molecular dynamics generated structures, Poisson-Boltzmann electrostatics have been applied to describe qualitative changes in the substrate/drug binding affinity on the protein surface and identify the viral DNA binding site. A viral DNA-integrase complex was proposed by means of molecular docking.
2. Computer simulation of oligo- and polysaccharides and biological membranes
In the past few years, the scientific community has shown a renewed interest for carbohydrates, driven in particular by their importance in biochemistry, industrial processes, and in the design of new materials. However, the mechanisms responsible for the specific properties of many polysaccharide-based systems are still only partially understood. To investigate these mechanisms at the molecular level, computer simulation represents a powerful tool complementary to experiment.
2.1. Trehalose as a protecting agent for biological structures
A variety of sugars are known to enhance the stability of biomaterials. Trehalose, a nonreducing disaccharide composed of two a [1-alpha-1] linked glucopyranose units, appears to be the most effective protectant. In nature, trehalose is present in large amounts (up to 20% of the dry mass) in certain desert plants and in some organisms such as the yeast Artemia salina capable of surviving in almost complete dehydration at elevated temperatures. Although the biological function of these organisms is interrupted under these conditions, trehalose stabilizes biological structures in the dehydrated form and restores them intact and functional as soon as the hydration and temperature conditions allow it, a phenomenon known as cryptobiose. The protective effect of trehalose acts at two levels: (i) the stabilization of membranes (cells, organelles) under conditions of very low hydration; (ii) the stabilization of biological macromolecules in the folded state under conditions which would normally lead to their denaturation. In other freeze-tolerant organisms, trehalose plays a similar role as a cryoprotectant. Despite the significant amount of experimental data, no available clear picture of the molecular mechanism has emerged yet. Three major hypotheses (increase of medium viscosity, water-trehalose hydrogen-bond replacement and by trapped water water coating) have been proposed to explain the stabilizing effect of trehalose on biomolcules. In order to investigate the nature of these molecular interactions, we have carried out two molecular dynamic simulations of the protein lysozyme in solution in the presence (0.5M at 25 and 100° C and 2.0M at 25° C) and absence of trehalose. Our findings allow us to identify role of viscosity as minor and address a hypothesis for the mechanism of protein-trehalose interaction.
2.2. In silico design and dynamics of lipopolysaccharide membranes
High concentration of metal ion complexes are known to be harmful because of their toxic and genotoxic effects. Improper disposal of wastes has caused soil and water contamination, threatening a number of ecosystems around the world. Ions such La, Eu, U, Cu and Fe were identified to bind in the cell wall of Pseudomonas aeruginosa. Lipopolysaccharides from the major constituent of the outer membrane of Gram-negative bacteria, and are believed to play a role in processes that govern microbial adsorption to mineral surfaces, and microbe-mediated oxidation/reduction. A computational molecular model of the outer membrane of P. aeruginosa was developed to study geochemical reactions at the level of the outer bacteria envelope. Conformational and dynamical information were extracted from this model to determine charge distribution along the membrane, transmembrane voltage, structural patterns in the sugar layer, etc. Analysis of its anharmonic motions were carried out in order to access details of the membrane internal flexibility. This model is being currently used to determine affinity of the membrane to several ions and mineral surfaces.
3. Force Field Development
Classical molecular mechanics parameters are widely used nowadays in biomolecular simulations addressing from pure dynamics to catalytic mechanisms to pharmacophore design. The development of a high quality parameter set is essential to an accurate description of dynamics, physical-chemical properties and inter-molecular interactions. In collaboration with Prof. Philippe Hünenberger, a Gromos-compatible carbohydrate and lipid force fields have been developed and are currently in the test phase. High level quantum chemistry data is used for derivation of the parameter sets in an efficient and consistent way.
4. Homochirality in Biological Systems
4.1. Origins of the Homochirality
The amplification of molecular dissymmetry by autocatalytic processes plays a central role in theories of the origin of molecular homochirality in our biota. The understanding of such phenomena is fundamental to our understanding of biogenesis itself. By computer simulations we have determined relative stabilities of oligoribotides containing D- and L-riboses, and peptide chains containing D- and L-residues. Mixed ribotides were found to be less stable than homochiral ones. This chiral effect is less noticeable in peptides chains. The results support that L-ribose act as a terminators to the template assisted growth of oligo-r-GD (enantiomeric cross inhibition, proposed by Joyce et al., 1987 PNAS, 84:4398) and consequently that RNA is the primitive chiral amplifier. It is proposed that the homochirality of a-amino acids was originated from stereochemical requirements of subsequent RNA-peptide interactions. Yet, a chemical pathway is proposed which could, under assumed prebiotic conditions, bypass the hindrance of homochiral growth.
4.2. Racemization in biological systems
Racemization of amino acids are known to be, in general, a very slow process commonly used to determine fossil age. However, aspartic acid residues (asp) in many peptides have racemization rates that can be very large when compared to other residues or with the free residue in solution. Among those peptides is the amyloid ß peptide associated with Alzheimers disease. Site specific racemizations seem to be associated with the appearance of senility plaques and cerebral hemorrhage. The racemization occurs in a three step pathway via an intermediate compound, succinimidyl residue (suc), which has been proposed as the limiting step for the reaction. Investigations of native and computer generated suc-asp replaced at positions 7 and 23 structures of the amyloid ß 1-28 peptide shows that the modification asp-suc leads to a significant increase of the water accessibility. These results can be used to explain and rationalize the racemization of aspartyl residues compared to other residues, since it goes undergo the asp-suc modification, thus allowing for a readly access of water at the racemization site. It is proposed that the behavior of the adjacent residues in the selectivity of the racemization is to control the water accessibility at the reactive site.
Prof. Dr. Philippe Hünenberger
Laboratory of Physical Chemistry
ETH Hönggerberg, HCI G233
CH-8093 Zürich, Switzerland
Phone : +41-1-632-5503
Fax : +41-1-632-1039
E-mail : firstname.lastname@example.org
Prof. Dr. Wilfred van Gunsteren
Physical Chemistry Institute
ETH Hönggerberg, HCI G
CH-8093 Zürich, Switzerland
Phone : +41-1-632 5501
Fax: +41-1-632 1039
E-mail : email@example.com
Dr. T. P. Straatsma
Technical Group Leader
Pacific Northwest National Laboratory
P.O. Box 999, K1-83
Richland, WA 99352, USA
Prof. Dr. Jim Briggs
Department of Biology & Biochemistry
University of Houston
4500 Calhoun Rd.
Houston, TX 77204-5001, USA
Prof. Dr. J. Andrew McCammon
Department of Chemistry and Biochemistry
University of California, San Diego
La Jolla, CA 92093-0365, USA
E-mail : firstname.lastname@example.org
Prof. Dr. Ricardo Ferreira
Departamento de Quimica Fundamental
Universidade Federal de Pernambuco
Cidade Universitaria, Recife 50670-901, Brazil