Quantitative Computer Simulations of Biomolecules: A Snapshot WEI YANG, 1,2,3 HUGH NYMEYER, 1,2,3 HUAN-XIANG ZHOU, 1,2,4 BERND BERG, 1,4 RAFAEL BRU ¨ SCHWEILER 2,3,5 1 School of Computational Science, Florida State University, Tallahassee, Florida 32306 2 Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida 32306 3 Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306 4 Department of Physics, Florida State University, Tallahassee, Florida 32306 5 National High Magnetic Field Laboratory, Florida State University, Tallahassee, Florida 32306 Received 2 May 2007; Revised 17 July 2007; Accepted 19 July 2007 DOI 10.1002/jcc.20819 Published online in Wiley InterScience (www.interscience.wiley.com). Abstract: A recent workshop titled ‘‘Quantitative Computational Biophysics’’ at Florida State University provided an overview of the state of the art in quantitative modeling of biomolecular systems. The presentations covered a wide range of interrelated topics, including the development and validation of force fields, the modeling of protein– protein interactions, the sampling of conformational space, and the assessment of equilibration and statistical errors. Substantial progress in all these areas was reported. q 2007 Wiley Periodicals, Inc. J Comput Chem 00: 000–000, 2007 Key words: improved MD force fields; enhanced sampling; protein–protein interactions; statistical convergence Introduction A workshop on ‘‘Quantitative Computational Biophysics’’ (QCBP2007), held February 17–21 at Florida State University, brought together scientists working in the field of biomolecular simulations and modeling to discuss their most recent research. Talks and posters presented at the workshop detailed substantial progress along different directions, which can be broadly divided into four areas: 1. New force fields and their validation by experiment; 2. Protein–protein interactions and electrostatics; 3. Enhanced sampling techniques; and 4. Statistical convergence. Most speakers reported on their research in one or several of these areas, including work that has not yet been published, which was often followed by extensive discussions. Because of the format of this review we focus on work that has appeared in the literature or is in press. New Force Fields and Their Validation by Experiment In a new generation of AMBER and CHARMM molecular mechanics force fields, the polypeptide backbone u,w Rama- chandran map was refined to provide an improved representation of the conformational ensemble of folded protein systems. 1–3 In the case of the AMBER99SB force field these modifications were made based on quantum-chemical energy calculations of glycine- and alanine tetrapeptides. 2 To assess the consequences of these force field modifications, comparison with high quality experimental data is essential. For sub-ns time-scale dynamics, NMR spin relaxation parameters are well suited for this task. It is quite common to compare model-free S 2 order parameters 4 of protein backbone NH bond vectors, reflecting the restriction in angular motion, with those extracted from MD trajectories. For short trajectories in the hundreds of ps using previous force fields, agreement with experiment was often found to be reason- able, but trajectories in the ns range and beyond, made possible by the ever increasing computer power, revealed overestimation of motion, especially for loop regions. 5 The recent modifications have largely overcome this problem, showing much better agree- ment. 1,2 Because NMR spin relaxation data are sensitive to the internal motional timescales, direct back-calculation of relaxa- tion parameters provides a stringent test of the trajectory and its underlying force field as is demonstrated by a MD simulation of ubiquitin using AMBER99SB in explicit SPC water. 6 Although overall molecular tumbling is still too rapid in the simulation, it Contract/grant sponsors: FSU School of Computational Science (SCS) and the Institute of Molecular Biophysics (IMB) Correspondence to: R. Bru ¨schweiler; e-mail: bruschweiler@magnet. fsu.edu q 2007 Wiley Periodicals, Inc.