Quantum mechanics simulation of protein dynamics on long timescale

Protein structure and dynamics are the keys to a wide range of problems in biology. In principle, both can be fully understood by using quantum mechan ics as the ultimate tool to unveil the molecular interactions involved. Ind eed, quantum mechanics of atoms and molecules have come to play a central r ole in chemistry and physics. In practice, however, direct application of q uantum mechanics to protein systems has been prohibited by the large molecu lar size of proteins. As a consequence, there is no general quantum mechani cal treatment that not only exceeds the accuracy of state-of-the-art empiri cal models for proteins but also maintains the efficiency needed for extens ive sampling in the conformational space, a requirement mandated by the com plexity of protein systems. Here we show that, given recent developments in methods, a general quantum mechanical-based treatment can be constructed. We report a molecular dynamics simulation of a protein, crambin, in solutio n for 350 ps in which we combine a semiempirical quantum-mechanical descrip tion of the entire protein with a description of the surrounding solvent, a nd solvent-protein interactions based on a molecular mechanics force field. Comparison with a recent very high-resolution crystal structure of crambin (Jelsch et al., Proc Natl Acad Sci USA 2000;102:2246-2251) shows that geom etrical detail is better reproduced in this simulation than when several al ternate molecular mechanics force fields are used to describe the entire sy stem of protein and solvent, even though the structure is no less flexible. Individual atomic charges deviate in both directions from "canonical" valu es, and some charge transfer is found between the N and C-termini. The capa bility of simulating protein dynamics on and beyond the few hundred ps time scale with a demonstrably accurate quantum mechanical model will bring new opportunities to extend our understanding of a range of basic processes in biology such as molecular recognition and enzyme catalysis. Proteins 2001;4 4:484-489. (C) 2001 Wiley-Liss, Inc.