An Efficient MCMC Approach to Energy Function Optimization in Protein Structure Prediction

Protein structure prediction is a critical problem linked to drug design, mutation detection, and protein synthesis, among other applications. To this end, evolutionary data has been used to build contact maps which are traditionally minimized as energy functions via gradient descent based schemes like the L-BFGS algorithm. In this paper we present what we call the Alternating Metropolis-Hastings (AMH) algorithm, which (a) significantly improves the performance of traditional MCMC methods, (b) is inherently parallelizable allowing significant hardware acceleration using GPU, and (c) can be integrated with the L-BFGS algorithm to improve its performance. The algorithm shows an improvement in energy of found structures of 8.17% to 61.04% (average 38.9%) over traditional MH and 0.53% to 17.75% (average 8.9%) over traditional MH with intermittent noisy restarts, tested across 9 proteins from recent CASP competitions. We go on to map the Alternating MH algorithm to a GPGPU which improves sampling rate by 277x and improves simulation time to a low energy protein prediction by 7.5x to 26.5x over CPU. We show that our approach can be incorporated into state-of-the-art protein prediction pipelines by applying it to both trRosetta2's energy function and the distogram component of Alphafold1's energy function. Finally, we note that specially designed probabilistic computers (or p-computers) can provide even better performance than GPUs for MCMC algorithms like the one discussed here.Comment: 10 pages, 4 figure

Autonomous Probabilistic Coprocessing with Petaflips per Second

In this paper we present a concrete design for a probabilistic (p-) computer based on a network of p-bits, robust classical entities fluctuating between -1 and +1, with probabilities that are controlled through an input constructed from the outputs of other p-bits. The architecture of this probabilistic computer is similar to a stochastic neural network with the p-bit playing the role of a binary stochastic neuron, but with one key difference: there is no sequencer used to enforce an ordering of p-bit updates, as is typically required. Instead, we explore \textit{sequencerless} designs where all p-bits are allowed to flip autonomously and demonstrate that such designs can allow ultrafast operation unconstrained by available clock speeds without compromising the solution's fidelity. Based on experimental results from a hardware benchmark of the autonomous design and benchmarked device models, we project that a nanomagnetic implementation can scale to achieve petaflips per second with millions of neurons. A key contribution of this paper is the focus on a hardware metric $-$ flips per second $-$ as a problem and substrate-independent figure-of-merit for an emerging class of hardware annealers known as Ising Machines. Much like the shrinking feature sizes of transistors that have continually driven Moore's Law, we believe that flips per second can be continually improved in later technology generations of a wide class of probabilistic, domain specific hardware.Comment: 13 pages, 8 figures, 1 tabl