Forum From the Wave Equation to Biomolecular Structure and Dynamics Suren A. Tatulian 1, * The multiscale models for complex chemical systems constitute a powerful computational tool to describe biomolecular structure and dynamics, including enzy- matic reactions. Here, the devel- opment of this method is presented as a miraculous chain of events, involving astoundingly lucky encounters of brilliant minds such as Planck, Schrödinger, Paul- ing, Karplus, Levitt, and Warshel. Computational methods have contributed significantly to the atomic-scale description of biomolecules. One of the major break- throughs in the field has been the develop- ment of multiscale models for complex chemical systems, marked by the 2013 Nobel Prize in Chemistry. This Forum explores the magni ficent Planck– Schrödinger–Pauling–Karplus–Levitt– Warshel trajectory and the associated pow- erful force field that led to this remarkable achievement. The story dates back to 1901 when two phenomenal events occurred: Max Planck published his energy quantization paper [1], thus launching the quantum theory, and Linus Pauling, who first applied quantum mechanics to molecular structure, was born. Quantum physics was furthered by many bright minds, notably Albert Einstein, Niels Bohr, Louis de Broglie, Werner Heisenberg, Wolfgang Pauli, Paul Dirac, and especially Erwin Schrödinger. Schrödinger’s life has been prolific in many ways. Along with his numerous love affairs, which produced many extramarital children (‘I put beauty before science,’ he wrote to Max Born), Schrödinger was fascinated by the ele- gance of the quantum theory. The result was his wave equation, i£@C r; t ð Þ=@t = ^ HC r; t ð Þ, published in 1926, exactly 25 years following Planck’s paper and relating the time evolution of the wavefunction (C ) with the system’s kinetic and potential energies through the Hamiltonian operator ( ^ H) [2–5]. It was a leap forward in the understanding of the inner workings of matter, and the reward was the 1933 Nobel Prize in Physics that Schrödinger shared with Dirac ‘for the discovery of new productive forms of atomic theory’. Schrödinger thus became Planck’s successor, his ‘scientific child’, by advancing wave mechanics into a mature theoretical framework. Moreover, Schrödinger succeeded Plank as chair of physics at the Friedrich Wilhelm Univer- sity in Berlin and, symbolically, was namesake of Planck’s son Erwin, who later was executed for participating in a plot against Adolf Hitler. Schrödinger would not be Schrödinger had he been satisfied by just one disci- pline. Biology, the physical basis of life, was his other passion. In his famous book What Is Life?, Schrödinger discusses the Heitler–London theory of chemical bond- ing and its role in molecular structure. ‘The “quantum jump” . . . is the transition from one . . . molecular configuration to another’ Schrödinger claims [6], compar- ing the discreteness of quantum energy levels with molecular rearrangements. Meanwhile, in the USA, a young fellow named Linus Pauling, with a BS in chemi- cal engineering and newly earned PhD in X-ray crystallography from Caltech, wins the Guggenheim award to study in Germany, Denmark, and Switzerland under Arnold Sommerfeld, Niels Bohr, and Erwin Schrödinger, respectively. What a treat! Pauling’s inquisitive mind absorbed the freshly tailored atomic and quantum theories like a sponge. Back in Caltech as assistant professor of theoret- ical chemistry, impregnated with the most advanced ideas of modern physics, he embarked on quantum mechanical anal- ysis of atomic and molecular orbitals, thus laying the groundwork of a new branch of science, quantum chemistry [7]. Having made fundamental contributions to the nature of chemical bonding, electronegativity, and orbital hybridiza- tion, Pauling developed an interest in the structure of biomolecules. In 1951, 25 years after the publication of Schrö- dinger’s wave equation, Pauling, together with Robert Corey and Herman Branson, described the main secondary structures of proteins (i.e., the a-helix and b-sheet [8,9]). Pauling thus became the ‘father’ of not only quantum chemistry but also molecular biology, as acknowledged by many prominent researchers, including Francis Crick. His discoveries were marked by the 1954 Nobel Prize in Chem- istry ‘for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances’. This triumphant period of Pauling’s life coincided with the PhD dissertation defense by his ‘most brilliant’ graduate student, Martin Karplus, Schrödinger’s compatriot by birth (both were born in Vienna, Austria). With a BS in chemistry and physics from Harvard, Karplus was interested in relating the theory of bonding to molecular structure. As a faculty mem- ber at the University of Illinois, he devel- oped the relationship between the vicinal coupling constant and dihedral angles, known as the Karplus equation and widely used in (bio)molecular NMR. Kar- plus returned to his alma mater, Harvard, as professor of chemistry, and restored his interest in his first love, biology (he TIBS 1473 No. of Pages 3 Trends in Biochemical Sciences, Month Year, Vol. xx, No. yy 1