Organisers

• Paolo Carloni (International School for Advanced Studies)
• David Beveridge (Wesleyan University)
• Alexandre M.J.J. Bonvin (Utrecht University)

Supports

 CECAM

 Psi-k

Description

The discovery of the structure of DNA in 1953, the subsequent elucidation of the genetic code and the mechanism of gene expression are collectively one of the most dramatic and significant advances in 20th century science. Not only was a set of ostensibly complex biological phenomena explained, but the very idea of what constitutes an explanation in biology was altered: a full understanding of a biological process henceforth needed to include a consideration of the structures and dynamics of the molecules and macro-molecules involved. Experimental methods from as x-ray crystallography as well as NMR and optical spectroscopy have yielded the 3D structures of many examples of DNAs, RNAs, both free and in complexes with ligands. While this information has carried the understanding of biological processes to unprecedented levels of rigor and resolution, these accomplishments have raised another class of fundamental questions: why do the structures assume their observed geometries, and exactly how does the structure and dynamics play a role in functional processes and relationships?



Research in this area is coming out based on quantum mechanical (QM) simulations molecular dynamics (MD) at the all-atom level, coarse grain representations, and at the other extreme, continuum electrostatics. The directions being pursued in the development of high quality computational models involve on one hand fully explicit all atom electronic structure and molecular dynamics calculations to establish the best possible computational models and provide benchmarks for future methods developments, and on the other to pursue the development of tractable models using reduced representations, coarse graining, and continuum or quasi-continuum methods. An active area of important current research is in the development of hybrid methods (combined QM and MD, MD based on hybrid explicit models and reduced representations of some components of the problem. A long- range hope is that hybrid multiscale models will make calculations of the even the most complex systems tractable on near-future generations of supercomputers.



The unique vantage point for theoretical physics and chemistry and computational modeling arises since in many systems of interest, experiments cannot isolate the contributions of various key components, nor determine their relative magnitudes of the various physical and chemical forces in order to identify the dominant contributions. Thus theoretical and computational modeling complements experiment in providing a detailed enough description a system to serve as a basis for deep understanding. However, for such research to be successful, the modeling procedures must be well validated and the methods for the treatment of atomic, molecular and mesoscale must be well validated and in hybrid studies well articulated so as to be as free as possible from methodological artifacts. There is a plethora of opportunities in this area for collaborations among computational modelers working at various scales of atomic and molecular resolution, and between modelers and experimentalists contributing cutting edge methods for structure determination based on diffraction and magnetic resonance, single molecule experiments, and new and novel ideas emerging form exotic molecular spectroscopies and synchrotron foot-printing experiments.



At this point in time, QM has reached the point that modeling the events involving electron and atom rearrangements taking place at the active sites of enzymes can be achieved MD simulations are now able to simulated hundreds of nanoseconds of explicit molecular motions, which have revealed new unforeseen complications involving the tendency of flexible molecules to exhibit distinct sub-states, each of which must be properly sampled. New advances in hybrid methodologies, combining QM and MD calculations and combining fully explicit and continuum models, particularly of electrostatics to treat problem of higher complexity, to obtain computational models of unprecedented levels of rigor and detail on what are now quite realistic representations of in vivo structures and processes. Just in the past year, the first QM/MM treatment of a drug DNA complex was achieved, MD simulations on the ion motions around DNA have finally been carried to convergence, and an international collaboration of modelers has produced a data base of MD simulations of all 136 unique tetramer DNA base pair that carries the potential to elucidate the outstanding 'sequence effects' problem and 'sequence context effects' problem and its contribution to DNA local deformations, axis curvature and ligand induced bending. MD on hundred base pair sequence of minicircles are in progress in several laboratories The first highly detailed simulations of protein DNA complexes hold the promise of improved understanding of binding affinities and specificities and both direct and indirect readout mechanisms in protein DNA recognition.

Scientific Objectives

This CECAM workshop gathers together those who have made recent significant contributions on the theoretical and computational side for mutual sharing of recent results and interactions with those who are performing state of the art experimental work in this area. The objective is cross-fertilization of knowledge and ideas as well as the development of possible new collaborations involving cross disciplinary theoretical, computational and experimental initiatives.



CECAM has for over 30 years been a key player in the development of new methods, creative computational strategies for approaching complex problems in computational molecular biophysics, and CECAM has been highly effective fostering what have become quite enduring international collaborations on problems beyond the scope of any one laboratory.



Our objectives in this workshop are also to bring together talented graduate students, postdoctoral fellows and young faculty beginning independent research programs with key senior scientists, and in particular to provide younger scientists with the opportunity to present their work and participate extensively in the allied discussions and planning of new researches.